Genetic Disorders and Biochemical Pathology — MCQs

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

Question 371: Which of the following diseases is associated with adenosine deaminase deficiency?

A. Chronic granulomatous disease
B. X-linked agammaglobulinemia
C. Severe combined immunodeficiency (SCID) (Correct Answer)
D. Transient hypogammaglobulinemia of infancy

Explanation: ### Explanation **Correct Option: C. Severe combined immunodeficiency (SCID)** **Underlying Biochemical Concept:** Adenosine Deaminase (ADA) is a critical enzyme in the purine salvage pathway. It converts adenosine to inosine and deoxyadenosine to deoxyinosine. In **ADA deficiency**, deoxyadenosine accumulates and is converted into **dATP**. High levels of dATP inhibit **ribonucleotide reductase**, the enzyme responsible for DNA synthesis. This toxicity primarily affects rapidly dividing lymphocytes (both T-cells and B-cells), leading to their apoptosis. The result is **Severe Combined Immunodeficiency (SCID)**, characterized by a complete lack of cell-mediated and humoral immunity. **Analysis of Incorrect Options:** * **A. Chronic Granulomatous Disease (CGD):** Caused by a deficiency in **NADPH oxidase**, leading to the inability of phagocytes to generate a respiratory burst (superoxide radicals). It results in recurrent infections with catalase-positive organisms. * **B. X-linked Agammaglobulinemia (Bruton’s):** Caused by a mutation in the **BTK gene** (Bruton Tyrosine Kinase), which leads to a failure of B-cell maturation. T-cell counts remain normal. * **D. Transient Hypogammaglobulinemia of Infancy:** A self-limiting delay in the infant's ability to produce their own IgG; it is not linked to enzyme deficiencies like ADA. **High-Yield Clinical Pearls for NEET-PG:** * **Inheritance:** ADA deficiency is the second most common cause of SCID and follows an **Autosomal Recessive** pattern (whereas the most common cause is X-linked SCID due to IL-2 receptor gamma chain mutation). * **Treatment:** It was the first disease treated with **Gene Therapy**. Other treatments include PEG-ADA replacement and Bone Marrow Transplant. * **Radiology:** Look for the **absence of a thymic shadow** on a chest X-ray in infants with SCID.

Question 372: NARP syndrome is a disorder of which cellular organelle?

A. Lysosome
B. Mitochondria (Correct Answer)
C. Nucleus
D. Cytosol

Explanation: **Explanation:** **NARP syndrome** (Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa) is a classic example of a **mitochondrial DNA (mtDNA) 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 impairs the organelle's ability to produce ATP via oxidative phosphorylation, leading to energy failure in tissues with high metabolic demands, such as the nervous system and retina. **Why other options are incorrect:** * **Lysosome:** Lysosomal storage disorders (e.g., Gaucher, Tay-Sachs) typically involve the accumulation of undigested substrates due to enzyme deficiencies, rather than primary ATP production failure. * **Nucleus:** While some mitochondrial proteins are encoded by nuclear DNA, NARP is specifically linked to mutations in the mitochondrial genome itself. * **Cytosol:** The cytosol is the site of glycolysis, but NARP involves the terminal stage of energy production (oxidative phosphorylation) which occurs exclusively within the mitochondria. **High-Yield Clinical Pearls for NEET-PG:** * **Maternal Inheritance:** Like most mtDNA disorders, NARP is inherited exclusively from the mother. * **The Leigh Disease Connection:** NARP and **Leigh Syndrome** (Subacute Necrotizing Encephalomyelopathy) represent a clinical spectrum. If the mutation load (heteroplasmy) is <90%, it manifests as NARP; if >90%, it manifests as the more severe Leigh Syndrome. * **Key Triad:** Remember the acronym: **N**eurogenic weakness, **A**taxia, **R**etinitis **P**igmentosa. * **Biochemical Marker:** Often associated with elevated lactate levels in blood or CSF due to impaired aerobic metabolism.

Question 373: All of the following diseases are due to an excessive number of glutamine residues in proteins, EXCEPT?

A. Huntington's chorea
B. Spinocerebellar ataxia
C. Myotonic dystrophy (Correct Answer)
D. Spinobulbar muscular atrophy

Explanation: This question tests your knowledge of **Trinucleotide Repeat Expansion** disorders, which are classified based on the specific repeat sequence and its location within the gene. ### **Explanation** The diseases listed are all trinucleotide repeat disorders, but they differ in the type of repeat: 1. **Myotonic Dystrophy (Type 1):** This is the correct answer because it is caused by a **CTG** repeat expansion in the 3' untranslated region (UTR) of the *DMPK* gene. Since the expansion occurs in a non-coding region, it does not result in a polyglutamine (polyQ) chain. Instead, it causes disease through RNA toxicity. 2. **Polyglutamine (polyQ) Diseases:** Options A, B, and D are all caused by **CAG** repeats within the **coding region (exon)** of the gene. In the genetic code, CAG codes for the amino acid **Glutamine**. Therefore, an expansion of CAG repeats leads to an abnormally long chain of glutamine residues in the protein, causing it to misfold and become toxic to neurons. * **Huntington’s Chorea:** CAG repeat in the *Huntingtin* gene. * **Spinocerebellar Ataxia (SCA):** Multiple types (e.g., SCA1, 2, 3) involve CAG repeats. * **Spinobulbar Muscular Atrophy (Kennedy Disease):** CAG repeat in the *Androgen Receptor* gene. ### **NEET-PG High-Yield Pearls** * **Anticipation:** This phenomenon, where the disease becomes more severe or has an earlier onset in successive generations, is a hallmark of trinucleotide repeat disorders. * **Friedreich Ataxia:** Unique because it is an **Autosomal Recessive** trinucleotide disorder (GAA repeat). * **Fragile X Syndrome:** Caused by **CGG** repeats in the 5' UTR of the *FMR1* gene, leading to gene silencing via methylation. * **Mnemonic for CAG (PolyQ):** "**H**untington **S**ings **A**t **B**ars" (**H**untington, **S**pinocerebellar Ataxia, **A**ndrogen receptor/Spinobulbar **B**ulbar atrophy).

Question 374: NARP syndrome is associated with which group of disorders?

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

Explanation: **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**, which encodes a subunit of ATP synthase (Complex V) in the mitochondrial oxidative phosphorylation pathway. This leads to impaired ATP production, primarily affecting tissues with high energy demands like the nervous system and retina. **Why the 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 or Pompe disease), primarily affecting the liver and skeletal muscles. * **Lysosomal storage diseases (LSDs):** These result from defects in lysosomal hydrolases (e.g., Gaucher or Tay-Sachs disease), leading to the accumulation of undigested macromolecules. * **Lipid storage diseases:** These are a subset of LSDs or peroxisomal disorders (e.g., Niemann-Pick) involving abnormal lipid metabolism, distinct from mitochondrial DNA mutations. **High-Yield Clinical Pearls for NEET-PG:** * **Maternal Inheritance:** Like most mitochondrial DNA (mtDNA) disorders, NARP is inherited exclusively from the mother. * **Heteroplasmy:** The severity of NARP depends on the ratio of mutant to wild-type mtDNA within cells. * **Leigh Syndrome Link:** If the MT-ATP6 mutation load is very high (>90%), the clinical presentation shifts from NARP to the more severe **Maternally Inherited Leigh Syndrome (MILS)**, characterized by subacute necrotizing encephalomyelopathy. * **Key Triad:** Always look for the combination of **Proximal weakness + Sensory ataxia + Salt-and-pepper retinopathy** in clinical vignettes.

Question 375: Increased ammonia level, normal pH, and high anion gap acidosis is seen in which of the following conditions?

A. Urea cycle defects
B. Galactosemia
C. Organic acidemia (Correct Answer)
D. Alkaptonuria

Explanation: **Explanation:** The clinical triad of **hyperammonemia, metabolic acidosis, and a high anion gap (HAGMA)** is the hallmark of **Organic Acidemias** (e.g., Methylmalonic acidemia, Propionic acidemia). 1. **Why Organic Acidemia is correct:** In these disorders, the accumulation of organic acid intermediates (like methylmalonate or propionate) directly increases the unmeasured anions, leading to **HAGMA**. Hyperammonemia occurs secondary to the inhibition of **N-acetylglutamate synthase (NAGS)** by the accumulated organic acyl-CoA esters. NAGS is essential for producing N-acetylglutamate, the obligatory activator of Carbamoyl Phosphate Synthetase I (CPS-I), the first step of the urea cycle. Thus, the urea cycle is "choked," leading to elevated ammonia. 2. **Why other options are incorrect:** * **Urea Cycle Defects:** These typically present with **severe hyperammonemia and respiratory alkalosis** (due to ammonia-induced hyperventilation). They do *not* cause a high anion gap metabolic acidosis. * **Galactosemia:** Presents with jaundice, hepatosplenomegaly, and cataracts. While it can cause a tubular acidosis (Fanconi syndrome), it does not typically present with the acute HAGMA/hyperammonemia triad. * **Alkaptonuria:** A relatively benign condition characterized by ochronosis (darkening of tissues) and dark urine upon standing. It does not cause acute metabolic crises or hyperammonemia. **High-Yield Clinical Pearls for NEET-PG:** * **Differentiating Factor:** If a neonate has hyperammonemia **without** acidosis, think Urea Cycle Disorder. If hyperammonemia is accompanied by **ketosis and HAGMA**, think Organic Acidemia. * **Common Enzyme Deficiencies:** Propionic acidemia (Propionyl-CoA carboxylase deficiency) and Methylmalonic acidemia (Methylmalonyl-CoA mutase deficiency). * **Management:** Immediate restriction of protein intake and administration of glucose to prevent catabolism.

Question 376: The gene for the folate carrier protein is located on which chromosome?

A. Chromosome 21 (Correct Answer)
B. Chromosome 5
C. Chromosome 10
D. Chromosome 9

Explanation: **Explanation:** The correct answer is **Chromosome 21**. The gene responsible for the **Reduced Folate Carrier 1 (RFC1)**, also known as SLC19A1, is located on the long arm of chromosome 21 (21q22.3). This protein is the primary transporter for moving folate (Vitamin B9) from the extracellular space into the cytoplasm. **Why Chromosome 21 is correct:** The localization of the folate carrier gene on Chromosome 21 has significant clinical implications in **Down Syndrome (Trisomy 21)**. Individuals with Down Syndrome have three copies of this gene, leading to increased expression of the folate transporter. This altered dosage affects intracellular folate pharmacokinetics, which is why children with Down Syndrome often exhibit increased sensitivity to folate antagonists like **Methotrexate** (used in treating ALL). **Analysis of Incorrect Options:** * **Chromosome 5:** Associated with the *MSH2* gene (Lynch syndrome) and the *APC* gene (Familial Adenomatous Polyposis), but not primary folate transport. * **Chromosome 10:** Contains the *PTEN* tumor suppressor gene. * **Chromosome 9:** Location of the *ABL* gene (translocated in Philadelphia chromosome) and the *FRDA* gene (Friedreich's ataxia). **High-Yield Clinical Pearls for NEET-PG:** 1. **Gene Dosage Effect:** The overexpression of RFC1 in Trisomy 21 leads to higher intracellular concentrations of methotrexate polyglutamates, increasing drug toxicity. 2. **Folate Metabolism:** Folate is essential for DNA synthesis (purine and pyrimidine synthesis). Deficiency leads to **Megaloblastic Anemia** and **Neural Tube Defects (NTDs)**. 3. **Absorption:** While RFC1 handles cellular uptake, the **Proton-Coupled Folate Transporter (PCFT)** on Chromosome 17 is responsible for intestinal folate absorption.

Question 377: Mutation in oxidative enzymes can lead to which of the following conditions?

A. Zellweger's syndrome (Correct Answer)
B. Gaucher's disease
C. Epidermolysis bullosa
D. Leber's neuropathy

Explanation: **Explanation:** **Zellweger’s Syndrome (Correct Answer):** Zellweger’s syndrome is a peroxisomal biogenesis disorder caused by mutations in **PEX genes**, which are essential for the import of enzymes into peroxisomes. Peroxisomes are the primary site for **oxidative reactions**, including the alpha-oxidation of branched-chain fatty acids and the beta-oxidation of very-long-chain fatty acids (VLCFA). A deficiency in these oxidative enzymes leads to the accumulation of VLCFAs and phytanic acid, causing severe neurological, hepatic, and renal impairment. **Why the other options are incorrect:** * **Gaucher’s disease:** This is a **Lysosomal Storage Disorder** caused by a deficiency of the enzyme *glucocerebrosidase*. It involves hydrolytic enzymes, not oxidative ones. * **Epidermolysis bullosa:** This is a group of genetic **connective tissue disorders** caused by mutations in structural proteins like *keratin* or *collagen*, leading to skin fragility and blistering. * **Leber’s Hereditary Optic Neuropathy (LHON):** While this involves the mitochondria (oxidative phosphorylation), it is specifically a **mitochondrial DNA mutation** affecting the respiratory chain complexes, typically presenting as sudden painless vision loss, rather than a general mutation in oxidative enzymes associated with peroxisomal biogenesis. **High-Yield Clinical Pearls for NEET-PG:** * **Zellweger Syndrome Triad:** Hypotonia ("floppy infant"), seizures, and hepatomegaly with distinctive craniofacial dysmorphism (high forehead). * **Biochemical Marker:** Elevated levels of **Very-Long-Chain Fatty Acids (VLCFA)** in the blood is the hallmark diagnostic finding. * **Peroxisome Function:** Remember the "3 Os": **O**xidation of VLCFA, **O**xygen radical detoxification (Catalase), and **O**rigination of plasmalogens (essential for myelin).

Question 378: The primary defect in Xeroderma pigmentosa is:

A. Formation of thymidine dimers (Correct Answer)
B. Poly ADP ribose polymerase is defective
C. Exonuclease is defective
D. Formation of adenine dimers

Explanation: **Explanation:** **Xeroderma Pigmentosum (XP)** is an autosomal recessive genetic disorder characterized by an extreme sensitivity to ultraviolet (UV) radiation. **1. Why Option A is Correct:** The primary pathology involves a defect in the **Nucleotide Excision Repair (NER)** pathway. When skin is exposed to UV light (specifically UV-B), it causes the covalent cross-linking of adjacent pyrimidine bases, most commonly leading to the **formation of thymidine dimers** (cyclobutane pyrimidine dimers). In healthy individuals, the NER mechanism identifies and removes these dimers. In XP patients, mutations in *XP genes* (XP-A through XP-G) result in the inability to repair this DNA damage, leading to mutations and a high risk of skin malignancies (Basal Cell Carcinoma, Squamous Cell Carcinoma, and Melanoma). **2. Why Other Options are Incorrect:** * **Option B:** Poly ADP ribose polymerase (PARP) is involved in **Base Excision Repair (BER)** and single-strand break repair, not the primary NER defect seen in XP. * **Option C:** While specific endonucleases initiate the NER process (nicking the DNA), "exonuclease" is a general term for enzymes that remove nucleotides from the ends of DNA. The specific deficiency in XP is the **UV-specific endonuclease** (excision nuclease), but the *primary defect/event* triggering the pathology is the formation of the dimers themselves. * **Option D:** Adenine dimers are not the characteristic lesion of UV damage; pyrimidine dimers (Thymine > Cytosine) are the hallmark. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Triad:** Photosensitivity, pigmentary changes (poikiloderma), and early-onset skin cancers. * **Neurological symptoms:** Seen in 20-30% of cases (e.g., De Sanctis-Cacchione syndrome). * **Key Enzyme:** UV-specific endonuclease deficiency is the most frequently tested biochemical defect. * **Must-know:** NER repairs "bulky" DNA lesions.

Question 379: Which of the following is NOT a feature of Phenylketonuria?

A. Severe mental retardation
B. Reduced tendon reflexes (Correct Answer)
C. Hypopigmentation of skin
D. Hair loss

Explanation: **Explanation:** Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of the enzyme **Phenylalanine Hydroxylase (PAH)** or its cofactor **Tetrahydrobiopterin (BH4)**. This leads to the accumulation of phenylalanine and its metabolites (phenylpyruvate, phenyllactate) in the body. **Why "Reduced tendon reflexes" is the correct answer:** In PKU, the neurological manifestation is typically **hyperreflexia** (increased tendon reflexes) and spasticity, rather than reduced reflexes. The accumulation of phenylalanine is neurotoxic, interfering with myelination and neurotransmitter synthesis, which leads to upper motor neuron signs and tremors. **Analysis of incorrect options:** * **Severe mental retardation:** This is a hallmark of untreated PKU. High levels of phenylalanine interfere with the transport of other large neutral amino acids into the brain, disrupting protein synthesis and brain development. * **Hypopigmentation of skin:** Phenylalanine is a competitive inhibitor of **Tyrosinase**, the key enzyme in melanin synthesis. Furthermore, the lack of Tyrosine (which becomes an essential amino acid in PKU) leads to decreased melanin, resulting in fair skin and blue eyes. * **Hair loss:** While not the primary feature, thinning of hair and light-colored (blonde) hair are common due to the systemic deficiency of melanin. **NEET-PG High-Yield Pearls:** * **Mousy/Musty Odor:** Caused by Phenylacetic acid in sweat and urine. * **Guthrie Test:** A bacterial inhibition assay used for neonatal screening. * **Dietary Management:** Restriction of Phenylalanine and supplementation of **Tyrosine** (which becomes "conditionally essential"). * **Maternal PKU:** If a mother doesn't control her Phe levels, the fetus may develop microcephaly and congenital heart defects (even if the fetus is heterozygous).

Question 380: A neonate presents with hypoglycemia and jaundice and is diagnosed to have a metabolic disorder. What is the most likely diagnosis?

A. Hypothyroidism
B. Glycogen storage disease
C. Galactosemia (Correct Answer)
D. None of the above

Explanation: **Explanation:** **Galactosemia** (specifically Classic Galactosemia due to GALT deficiency) is the most likely diagnosis because it classically presents in the **neonatal period** shortly after the introduction of milk (lactose). 1. **Why Galactosemia is correct:** The accumulation of Galactose-1-phosphate in the liver causes hepatotoxicity, leading to **jaundice** and hepatomegaly. **Hypoglycemia** occurs because high levels of Galactose-1-phosphate inhibit *phosphoglucomutase* and *glucose-6-phosphatase*, impairing both glycogenolysis and gluconeogenesis. 2. **Why other options are incorrect:** * **Hypothyroidism:** While it can cause prolonged physiological jaundice in neonates, it typically presents with lethargy, constipation, and a large fontanelle, rather than acute hypoglycemia. * **Glycogen Storage Disease (GSD):** While GSD Type I (von Gierke) causes severe hypoglycemia and hepatomegaly, it usually presents at **3–6 months** of age when feeding intervals increase. It does not typically present with conjugated jaundice in the immediate neonatal period. **High-Yield Clinical Pearls for NEET-PG:** * **Enzyme Deficiency:** Most common is **Galactose-1-phosphate uridyltransferase (GALT)**. * **Key Clinical Triad:** Cataracts (due to *galactitol* accumulation in the lens), Jaundice, and Liver failure. * **Diagnostic Clue:** Presence of **reducing sugars** in urine (Clinitest positive) but a negative glucose oxidase test (Dipstick negative). * **Infection Risk:** These neonates are at a significantly increased risk of **E. coli sepsis**. * **Management:** Immediate withdrawal of breast milk/lactose-containing formula and switching to soy-based formula.

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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