Genetic Disorders and Biochemical Pathology — MCQs

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

Question 491: Which of the following statements is FALSE about alkaptonuria?

A. Genitourinary system is not involved. (Correct Answer)
B. There is a deficiency of homogentisic acid oxidase.
C. The urine turns black.
D. Calcification occurs in vertebral bodies.

Explanation: **Explanation:** Alkaptonuria is an autosomal recessive disorder of tyrosine metabolism caused by a deficiency of the enzyme **homogentisic acid oxidase**. This deficiency leads to the accumulation of homogentisic acid (HGA) in the blood and tissues. **Why Option A is the Correct (False) Statement:** The statement "Genitourinary system is not involved" is **false** because the genitourinary system is frequently affected. Excess HGA is excreted in the urine, and its oxidation products can lead to the formation of **dark-colored renal stones (calculi)** and prostatic stones in males. Therefore, the GU system is indeed involved. **Analysis of Other Options:** * **Option B:** This is a true statement. The primary biochemical defect is the lack of homogentisic acid oxidase, which normally converts HGA into maleylacetoacetate. * **Option C:** This is a true statement. When urine containing HGA is left standing or exposed to an alkaline environment, it undergoes oxidation and polymerization to form a melanin-like pigment, turning the **urine black**. * **Option D:** This is a true statement. Chronic accumulation of HGA leads to **Ochronosis** (pigment deposition in connective tissues). This causes severe arthritis and **calcification of intervertebral discs**, leading to a characteristic "bamboo spine" appearance on X-rays. **High-Yield Clinical Pearls for NEET-PG:** * **Triad of Alkaptonuria:** Homogentisic aciduria (black urine), Ochronosis (blue-black pigmentation of ear cartilage/sclera), and Arthritis. * **Diagnosis:** Ferric chloride test (urine turns transiently deep blue) or Silver Nitrate test. * **Management:** Low protein diet (restriction of Phenylalanine and Tyrosine) and **Nitisinone**, which inhibits the enzyme 4-hydroxyphenylpyruvate dioxygenase to reduce HGA production.

Question 492: Sickle cell anemia is the clinical manifestation of homozygous genes for an abnormal hemoglobin molecule. What is the event responsible for the mutation in the B chain?

A. Insertion
B. Deletion
C. Nondisjunction
D. Point mutation (Correct Answer)

Explanation: **Explanation:** Sickle cell anemia (HbS) is a classic example of a **Point Mutation**, specifically a **Missense Mutation**. The molecular basis involves a single base substitution in the DNA sequence of the $\beta$-globin gene on chromosome 11. **Why Point Mutation is Correct:** The mutation occurs at the **6th codon** of the $\beta$-chain, where the triplet **GAG** (encoding Glutamic acid) is changed to **GTG** (encoding Valine). This single nucleotide change (Adenine to Thymine) results in the replacement of a polar, hydrophilic amino acid (Glutamic acid) with a non-polar, hydrophobic amino acid (Valine). This change causes the hemoglobin to polymerize under deoxygenated conditions, leading to the characteristic "sickling" of red blood cells. **Why Other Options are Incorrect:** * **Insertion/Deletion:** These typically lead to **Frameshift Mutations**, which alter the entire reading frame of the protein from the point of mutation. HbS involves a substitution, not a change in the number of nucleotides. * **Nondisjunction:** This is a failure of homologous chromosomes or sister chromatids to separate during cell division, leading to **Aneuploidy** (e.g., Trisomy 21). It is a chromosomal abnormality, not a gene-level mutation. **NEET-PG High-Yield Pearls:** * **Inheritance:** Autosomal Recessive. * **Electrophoresis:** HbS moves **slowest** toward the anode compared to HbA and HbC (mnemonic: **A** Fat **S**low **C**ar). * **Protective Effect:** Heterozygotes (Sickle cell trait) have a selective advantage against *Plasmodium falciparum* malaria. * **Sticky Patches:** Deoxygenated HbS molecules stick together via hydrophobic interactions between Valine at position 6 and the Phe 85/Leu 88 pocket of an adjacent $\beta$-chain.

Question 493: A patient presents with retinoblastoma, having a single tumor in one eye. Which of the following tests could be used to determine whether this is a heritable or sporadic tumor?

A. DNA footprinting
B. Fluorescence-activated cell sorting (FACS)
C. Northern blotting
D. Polymerase Chain Reaction (PCR) (Correct Answer)

Explanation: ### Explanation **Correct Option: D. Polymerase Chain Reaction (PCR)** Retinoblastoma is caused by mutations in the **RB1 gene** (a tumor suppressor gene) on chromosome 13q14. According to **Knudson’s "Two-Hit" Hypothesis**, both alleles must be inactivated for a tumor to develop. * **Heritable (Germline) form:** The first mutation is present in every cell of the body (germline). A second somatic hit occurs in the retinal cell. * **Sporadic form:** Both mutations occur somatically in a single retinal cell; peripheral cells (like blood) remain wild-type. **PCR** is used to amplify DNA from peripheral blood leukocytes. If PCR followed by sequencing reveals an *RB1* mutation in the blood, the condition is **heritable**. If the blood DNA is normal but the tumor DNA shows mutations, it is **sporadic**. **Why Incorrect Options are Wrong:** * **A. DNA Footprinting:** Used to identify the specific site where a protein (like a transcription factor) binds to a DNA sequence. It is not used for clinical mutation screening. * **B. FACS:** A technique used to sort cells based on size, granularity, or surface markers (e.g., CD4 counts in HIV). It does not analyze specific gene mutations. * **C. Northern Blotting:** Used to detect and quantify **RNA** levels. While it measures gene expression, it is not the standard for detecting the primary genomic DNA mutations required to differentiate heritability in Retinoblastoma. **High-Yield Clinical Pearls for NEET-PG:** * **Knudson’s Hypothesis:** Explains why heritable cases are often bilateral/multifocal (only one "hit" needed) and sporadic cases are usually unilateral (two "hits" needed in the same cell). * **RB Protein Function:** It regulates the **G1 to S phase** transition by binding to and inhibiting the **E2F transcription factor**. * **Associated Tumors:** Patients with germline *RB1* mutations have a high risk of developing **Osteosarcoma** later in life.

Question 494: Which of the following is FALSE regarding Hartnup disease?

A. Defect in neutral amino acid transport
B. Mental retardation is the common presentation (Correct Answer)
C. Most children are asymptomatic
D. Photosensitivity

Explanation: **Explanation:** **Hartnup disease** is an autosomal recessive disorder caused by a mutation in the **SLC6A19 gene**, which encodes a sodium-dependent **neutral amino acid transporter** located in the proximal renal tubules and the intestinal mucosa. 1. **Why Option B is False (The Correct Answer):** While neurological symptoms can occur during acute flares, **mental retardation is NOT a common or characteristic presentation** of Hartnup disease. Most affected individuals lead normal lives without cognitive impairment. If neurological symptoms appear, they usually manifest as intermittent cerebellar ataxia or emotional lability during periods of severe nutritional deficiency. 2. **Why other options are True:** * **Option A:** The primary pathology is a defect in the transport of **neutral amino acids** (e.g., Tryptophan, Alanine, Serine) in the gut and kidneys. * **Option C:** Interestingly, **most children remain asymptomatic** because dietary protein intake in modern diets is usually sufficient to compensate for the transport losses. * **Option D:** **Photosensitivity** is a hallmark. Tryptophan is a precursor for **Niacin (Vitamin B3)**. Malabsorption of tryptophan leads to niacin deficiency, resulting in a **pellagra-like skin rash** (dermatitis in sun-exposed areas). **High-Yield Clinical Pearls for NEET-PG:** * **Biochemical Marker:** Diagnosis is confirmed by **neutral aminoaciduria** (detected via chromatography). * **The "3 Ds" of Pellagra:** Dermatitis, Diarrhea, and Dementia (though in Hartnup, the full triad is rare). * **Treatment:** High-protein diet and **Nicotinamide (Vitamin B3)** supplementation. * **Differential Diagnosis:** Always differentiate from dietary Pellagra; Hartnup will show amino acids in the urine, whereas dietary deficiency will not.

Question 495: All of the following are considered Glycogen Storage Disorders EXCEPT?

A. Anderson's disease
B. Her's disease
C. Scheie's disease (Correct Answer)
D. Tarui's disease

Explanation: **Explanation:** The correct answer is **Scheie’s disease** because it is a **Mucopolysaccharidosis (MPS Type I-S)**, not a Glycogen Storage Disorder (GSD). It is caused by a deficiency of the lysosomal enzyme **α-L-iduronidase**, leading to the accumulation of dermatan sulfate and heparan sulfate. Clinically, it is the mildest form of MPS I, characterized by corneal clouding, stiff joints, and a normal lifespan, unlike the more severe Hurler syndrome. **Analysis of Incorrect Options (GSDs):** * **Anderson’s disease (GSD Type IV):** Caused by a deficiency of the **Branching enzyme**. It leads to the accumulation of abnormal glycogen with long outer chains (amylopectin-like), resulting in early-onset liver cirrhosis and heart failure. * **Her’s disease (GSD Type VI):** Caused by a deficiency of **Liver Phosphorylase**. It typically presents with hepatomegaly and mild hypoglycemia, as the liver cannot break down glycogen into glucose-1-phosphate. * **Tarui’s disease (GSD Type VII):** Caused by a deficiency of **Muscle Phosphofructokinase (PFK)**. It presents similarly to McArdle’s disease (Type V) with exercise-induced muscle cramps and myoglobinuria, but may also feature hemolytic anemia. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic for GSDs:** "**V**on Gierke, **P**ompe, **C**ori, **A**nderson, **M**cArdle, **H**ers, **T**arui" (**V**ery **P**oor **C**arbohydrate **A**dabolism **M**akes **H**umans **T**ired). * **Pompe Disease (Type II):** The only GSD that is also a **Lysosomal Storage Disorder** (Acid Maltase deficiency). * **Von Gierke (Type I):** Most common GSD; presents with severe hypoglycemia, lactic acidosis, and hyperuricemia.

Question 496: What type of mutation is characteristic of sickle cell anemia?

A. Silent mutation
B. Missense mutation (Correct Answer)
C. Nonsense mutation
D. Frameshift mutation

Explanation: ### Explanation **Sickle Cell Anemia (SCA)** is an autosomal recessive disorder caused by a specific **point mutation** in the $\beta$-globin gene located on chromosome 11. **Why Missense Mutation is Correct:** A missense mutation occurs when a single nucleotide substitution results in a different amino acid being incorporated into the protein. In SCA, there is a substitution of **Adenine by Thymine (GAG $\rightarrow$ GTG)** at the 6th codon. This causes **Glutamic acid** (a polar, negatively charged amino acid) to be replaced by **Valine** (a non-polar, hydrophobic amino acid). This change creates "sticky patches" on the hemoglobin molecule (HbS), leading to polymerization under deoxygenated conditions and the characteristic sickling of RBCs. **Analysis of Incorrect Options:** * **A. Silent Mutation:** A change in the DNA sequence that does not change the amino acid produced (due to the degeneracy of the genetic code). This would result in a normal protein. * **C. Nonsense Mutation:** A point mutation that creates a premature stop codon (UAG, UAA, or UGA), leading to a truncated, usually non-functional protein (e.g., some forms of $\beta^0$ thalassemia). * **D. Frameshift Mutation:** Caused by insertions or deletions of nucleotides (not in multiples of three), which shifts the reading frame and alters all subsequent amino acids (e.g., Tay-Sachs disease). **High-Yield Clinical Pearls for NEET-PG:** * **Electrophoresis:** On alkaline electrophoresis, HbS moves **slower** than HbA toward the anode because it has lost two negative charges (one per $\beta$ chain). * **Protective Effect:** Heterozygotes (Sickle cell trait) show resistance to *Plasmodium falciparum* malaria. * **Metabolic Trigger:** Sickling is precipitated by hypoxia, acidosis, dehydration, and increased 2,3-BPG.

Question 497: NARP syndrome is a type of:

A. Mitochondrial function disorder (Correct Answer)
B. Glycogen storage disorder
C. Lysosomal storage disorder
D. Lipid storage disorder

Explanation: **Explanation:** **NARP syndrome** (Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa) is a classic example of a **mitochondrial function disorder**. It is caused by a point mutation in the **MT-ATP6 gene**, which encodes a subunit of the mitochondrial ATP synthase (Complex V). This mutation disrupts the oxidative phosphorylation pathway, leading to impaired ATP production and cellular energy failure, primarily affecting high-energy-demand tissues like the brain and nerves. **Analysis of Options:** * **A. Mitochondrial function disorder (Correct):** NARP follows maternal inheritance. Interestingly, if the mutation load (heteroplasmy) exceeds 90%, it manifests as the more severe **Leigh Syndrome** (subacute necrotizing encephalomyelopathy). * **B. Glycogen storage disorder:** These involve deficiencies in enzymes regulating glycogen synthesis or breakdown (e.g., Von Gierke or Pompe disease), typically presenting with hepatomegaly or hypoglycemia. * **C. Lysosomal storage disorder:** These result from defects in lysosomal acid hydrolases (e.g., Gaucher or Tay-Sachs disease), leading to the accumulation of undigested macromolecules. * **D. Lipid storage disorder:** These are a subset of lysosomal or metabolic disorders (e.g., Niemann-Pick) involving abnormal lipid accumulation, not primary ATP synthesis defects. **High-Yield Clinical Pearls for NEET-PG:** * **Inheritance:** Maternal (Mitochondrial DNA). * **Key Triad:** Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa. * **Genetics:** Mutation at **position 8993** (T>G or T>C) in the MT-ATP6 gene. * **Heteroplasmy:** The clinical severity depends on the ratio of mutant to wild-type mtDNA; NARP and Leigh syndrome exist on a clinical continuum based on this percentage.

Question 498: All of the following are features of Lesch-Nyhan syndrome EXCEPT:

A. Hyperuricaemia
B. Self-mutilation
C. Mental retardation
D. Immunodeficiency (Correct Answer)

Explanation: **Explanation:** **Lesch-Nyhan Syndrome (LNS)** is an 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, which recycles hypoxanthine and guanine into IMP and GMP. 1. **Why Immunodeficiency is the correct answer:** Immunodeficiency is **not** a feature of Lesch-Nyhan syndrome. While purine metabolism defects can cause immune issues (e.g., Adenosine Deaminase deficiency leads to SCID), HGPRT deficiency specifically affects the nervous system and uric acid metabolism without compromising the immune system. 2. **Analysis of incorrect options:** * **Hyperuricaemia (A):** Without HGPRT, purines cannot be salvaged and are instead degraded into uric acid. This leads to severe hyperuricemia, gouty arthritis, and nephrolithiasis (orange sand in diapers). * **Self-mutilation (B):** This is the hallmark behavioral feature of LNS. Patients exhibit compulsive biting of lips and fingers. * **Mental retardation (C):** The deficiency of HGPRT in the basal ganglia leads to neurological dysfunction, including intellectual disability, spasticity, and choreoathetosis. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic (HGPRT):** **H**yperuricemia, **G**out, **P**issed off (aggression/self-mutilation), **R**etardation (intellectual disability), **D**ys**T**onia. * **Inheritance:** X-linked recessive (affects males). * **Biochemical marker:** Increased levels of **PRPP** (Phosphoribosyl pyrophosphate) and increased de novo purine synthesis. * **Treatment:** Allopurinol or Febuxostat (manages uric acid but does not fix neurological symptoms).

Question 499: Symptoms of Huntington's disease mimic which of the following?

A. Beri-Beri
B. Pellagra (Correct Answer)
C. Kwashiorkor
D. Korsakoff psychosis

Explanation: **Explanation:** The correct answer is **Pellagra**. **Why Pellagra?** Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by the expansion of CAG repeats. The clinical hallmark of HD is the **"3 Ds"** of cognitive and behavioral decline: **Dementia, Depression (or behavioral changes), and Dyskinesia (Chorea)**. Pellagra, caused by a deficiency of **Niacin (Vitamin B3)**, is classically characterized by its own "3 Ds": **Dermatitis, Diarrhea, and Dementia**. The neurological manifestations of Pellagra—specifically the progressive dementia, irritability, and psychiatric symptoms—closely mimic the cognitive decline and behavioral disturbances seen in the early to middle stages of Huntington’s disease. **Analysis of Incorrect Options:** * **Beri-Beri (Vitamin B1 deficiency):** Presents as high-output heart failure (Wet Beri-Beri) or peripheral neuropathy (Dry Beri-Beri). While it involves the nervous system, it lacks the specific choreiform movements and progressive cortical dementia typical of HD. * **Kwashiorkor:** A form of severe protein-energy malnutrition characterized by edema, "flaky paint" dermatosis, and fatty liver. It does not present with the neurodegenerative features of HD. * **Korsakoff Psychosis:** Also due to Thiamine (B1) deficiency, it is characterized by anterograde amnesia and **confabulation**. While it involves cognitive impairment, it is distinct from the motor symptoms (chorea) and global dementia of HD. **NEET-PG High-Yield Pearls:** * **Huntington’s Genetics:** CAG repeat expansion on **Chromosome 4** (Huntingtin gene). It shows **Anticipation**, especially via paternal transmission. * **Pathology:** Atrophy of the **Caudate Nucleus** and Putamen (Striatum), leading to "boxcar ventricles" on imaging. * **Biochemical Shift:** Decreased levels of **GABA** and **Acetylcholine** in the basal ganglia, with a relative increase in Dopamine.

Question 500: Hemochromatosis is a defect in the metabolism of which element?

A. Iron (Correct Answer)
B. Copper
C. Magnesium
D. Calcium

Explanation: **Explanation** **Hemochromatosis** is a hereditary disorder of **Iron** metabolism characterized by excessive intestinal absorption of dietary iron. This leads to the progressive accumulation of iron in various organs, primarily the liver, pancreas, heart, and joints. **Why Iron is Correct:** The most common form (Hereditary Hemochromatosis) is caused by a mutation in the **HFE gene** (most commonly C282Y). This mutation results in a deficiency of **Hepcidin**, the master regulator of iron homeostasis. Low hepcidin levels lead to increased ferroportin activity on enterocytes, causing uncontrolled iron entry into the plasma. This excess iron is deposited as **hemosiderin**, causing oxidative tissue damage. **Why Other Options are Incorrect:** * **Copper:** Defects in copper metabolism lead to **Wilson’s Disease** (ATP7B mutation), characterized by copper accumulation in the liver and basal ganglia (Kayser-Fleischer rings). * **Magnesium:** Disorders of magnesium involve renal wasting or malabsorption (e.g., Gitelman syndrome), but no primary "storage" disease like hemochromatosis exists for magnesium. * **Calcium:** Calcium metabolism defects typically relate to parathyroid dysfunction or Vitamin D issues, leading to hypercalcemia or hypocalcemia, not systemic storage overload. **High-Yield Clinical Pearls for NEET-PG:** * **Classic Triad:** "Bronze Diabetes" (Skin hyperpigmentation, Diabetes Mellitus, and Cirrhosis). * **Diagnosis:** Best initial test is **Transferrin Saturation** (>45%); Gold standard is **MRI (T2*)** or Liver Biopsy (Perls' Prussian Blue stain). * **Treatment:** Therapeutic phlebotomy is the mainstay of management. * **Association:** Patients are at a significantly increased risk of **Hepatocellular Carcinoma (HCC)**.

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

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Hemoglobinopathies

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Porphyrias

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Biochemical Markers for Disease Diagnosis

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Newborn Screening for Genetic Disorders

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Enzyme Replacement Therapy

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