Genetic Disorders and Biochemical Pathology — MCQs

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

Question 351: Which of the following is a feature of Phenylketonuria?

A. Loss of deep tendon reflexes
B. Mental retardation (Correct Answer)
C. Macrocephaly
D. All of the above

Explanation: **Explanation:** **Phenylketonuria (PKU)** is an autosomal recessive inborn error of metabolism caused by a deficiency of the enzyme **phenylalanine hydroxylase (PAH)** or its cofactor, **tetrahydrobiopterin (BH4)**. This deficiency leads to the accumulation of phenylalanine and its metabolites (phenylpyruvate, phenyllactate) in the blood and tissues. **Why Mental Retardation is Correct:** The hallmark of untreated PKU is severe **intellectual disability (mental retardation)**. High levels of phenylalanine are neurotoxic; they interfere with the transport of other large neutral amino acids across the blood-brain barrier and inhibit the synthesis of neurotransmitters like dopamine and serotonin. If not managed with a low-phenylalanine diet shortly after birth, irreversible brain damage occurs. **Why Other Options are Incorrect:** * **Loss of deep tendon reflexes:** PKU is typically associated with **hyperreflexia** and increased muscle tone (spasticity) rather than a loss of reflexes. * **Macrocephaly:** Patients with untreated PKU often exhibit **microcephaly** (small head size) due to impaired brain growth and myelination, not macrocephaly. **High-Yield Clinical Pearls for NEET-PG:** * **Mousy/Musty Odor:** Caused by phenylacetic acid in sweat and urine. * **Hypopigmentation:** Phenylalanine inhibits tyrosinase, leading to fair skin, blonde hair, and blue eyes. * **Diagnosis:** Guthrie test (bacterial inhibition assay) or Tandem Mass Spectrometry (TMS) for neonatal screening. * **Maternal PKU:** If a mother with PKU doesn't maintain a diet during pregnancy, the fetus may suffer from microcephaly, mental retardation, and congenital heart defects (even if the fetus is heterozygous).

Question 352: Phenylketonuria is inherited in which pattern?

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

Explanation: **Explanation:** **Phenylketonuria (PKU)** is a classic example of an **Autosomal Recessive (AR)** disorder. It is primarily caused by a deficiency of the hepatic enzyme **Phenylalanine Hydroxylase (PAH)**, or less commonly, its cofactor **Tetrahydrobiopterin (BH4)**. In AR inheritance, an individual must inherit two mutated alleles (one from each carrier parent) to manifest the disease. This pattern is typical for most inborn errors of metabolism involving enzyme deficiencies, as a single functional gene (in heterozygotes) usually produces enough enzyme to maintain normal metabolic function. **Analysis of Incorrect Options:** * **Autosomal Dominant (AD):** These disorders typically involve structural proteins (e.g., Marfan syndrome) or receptors (e.g., Familial Hypercholesterolemia). A single mutant allele is sufficient to cause the phenotype. * **X-linked Dominant:** These are rare (e.g., Alport syndrome, Vitamin D-resistant rickets) and affect both males and females, often being more severe in males. * **X-linked Recessive:** These primarily affect males (e.g., Hemophilia, G6PD deficiency). PKU affects both sexes equally, ruling out X-linked inheritance. **High-Yield Clinical Pearls for NEET-PG:** * **Biochemical Hallmark:** Accumulation of Phenylalanine and its metabolites (Phenylpyruvate, Phenyllactate, Phenylacetate) in blood and urine. * **Clinical Presentation:** Intellectual disability, **"Mousy/Musty" body odor**, microcephaly, and hypopigmentation (due to decreased melanin synthesis). * **Diagnosis:** Guthrie Test (bacterial inhibition assay) or Tandem Mass Spectrometry (TMS) for newborn screening. * **Management:** Lifelong restriction of dietary Phenylalanine; Tyrosine becomes an **essential amino acid** for these patients.

Question 353: What is the triplet repeat sequence associated with Huntington's disease?

A. CTG
B. CGG
C. CAG (Correct Answer)
D. GAA

Explanation: **Explanation:** **Huntington’s Disease (HD)** is an autosomal dominant neurodegenerative disorder characterized by the expansion of a trinucleotide repeat. The correct answer is **CAG** (Option C). This repeat occurs in the *HTT* gene on chromosome 4, which encodes the protein huntingtin. The **CAG** sequence codes for the amino acid **Glutamine**. Therefore, HD is classified as a **polyglutamine (polyQ) disease**. The expanded polyglutamine tract leads to a "gain-of-function" mutation where the mutant huntingtin protein aggregates, causing neuronal death, particularly in the caudate nucleus and putamen (striatum). **Analysis of Incorrect Options:** * **A. CTG:** Associated with **Myotonic Dystrophy** (Type 1). It affects the *DMPK* gene. (Mnemonic: **C**ataract, **T**oupee/Balding, **G**onadal atrophy). * **B. CGG:** Associated with **Fragile X Syndrome**. It occurs in the *FMR1* gene. (Mnemonic: **C**hin/Giant Gonads). * **D. GAA:** Associated with **Friedreich Ataxia**. It occurs in the *FXN* gene encoding frataxin. (Mnemonic: Friedreich is **GAA**y/Gait Ataxia Always). **High-Yield Clinical Pearls for NEET-PG:** * **Anticipation:** HD shows anticipation (earlier onset/increased severity in successive generations), typically when inherited from the **father** (paternal transmission). * **Threshold:** Normal repeats are <26; >40 repeats are fully penetrant for the disease. * **Clinical Triad:** Chorea, Dementia, and Psychiatric symptoms (depression/aggression). * **Imaging:** "Boxcar ventricles" on MRI due to atrophy of the caudate nucleus.

Question 354: A 30-year-old female presents with bluish-black discoloration of the sclera and pinna for the last 4 months. Her urine turns black on standing. What is the most likely diagnosis?

A. Phenylketonuria
B. Alkaptonuria (Correct Answer)
C. Tyrosinemia
D. Maple syrup urine disease

Explanation: ### Explanation **Correct Option: B. Alkaptonuria** Alkaptonuria is an autosomal recessive disorder caused by a deficiency of the enzyme **Homogentisate Oxidase**. This enzyme is responsible for converting homogentisic acid (HGA) into maleylacetoacetate in the phenylalanine-tyrosine catabolic pathway. The clinical presentation in this case is classic: 1. **Urine turning black on standing:** Excess HGA is excreted in the urine. When exposed to air, it undergoes oxidation and polymerization to form a melanin-like pigment. 2. **Ochronosis:** This refers to the deposition of the dark pigment in connective tissues. It typically manifests as **bluish-black discoloration** of the sclera and the cartilage of the pinna (ear). 3. **Alkaptonuric Arthritis:** Long-term deposition in large joints and the spine leads to debilitating arthritis, usually appearing in the 3rd or 4th decade of life. --- ### Why the other options are incorrect: * **A. Phenylketonuria (PKU):** Caused by Phenylalanine Hydroxylase deficiency. It presents with intellectual disability, seizures, and a "mousy" body odor. It does not cause dark pigmentation or urine that turns black. * **C. Tyrosinemia:** Type I (Hepatorenal) presents with liver failure, cabbage-like odor, and renal rickets. Type II (Oculocutaneous) presents with palmoplantar keratosis and corneal ulcers. Neither causes ochronosis. * **D. Maple Syrup Urine Disease (MSUD):** Caused by a deficiency in the Branched-Chain Alpha-Keto Acid Dehydrogenase complex. It presents in neonates with poor feeding, vomiting, and urine that smells like burnt sugar/maple syrup. --- ### High-Yield Clinical Pearls for NEET-PG: * **Diagnostic Test:** Addition of **Benedict’s reagent** to urine gives a strongly positive (yellow/orange) result due to the reducing nature of HGA, but the supernatant turns black. * **Ferric Chloride Test:** Urine gives a transient deep blue/green color. * **Treatment:** Low protein diet (restricting Phenylalanine and Tyrosine) and **Nitisinone**, which inhibits 4-hydroxyphenylpyruvate dioxygenase, preventing HGA formation.

Question 355: Which of the following is an X-linked recessive disorder?

A. Wiskott-Aldrich Syndrome (Correct Answer)
B. Rett Syndrome
C. Thalassemia
D. Alkaptonuria

Explanation: **Explanation:** **Wiskott-Aldrich Syndrome (WAS)** is the correct answer. It is an **X-linked recessive** primary immunodeficiency characterized by the triad of **thrombocytopenia** (with small platelets), **eczema**, and **recurrent infections**. It is caused by a mutation in the *WAS* gene, which encodes the Wiskott-Aldrich Syndrome Protein (WASP), essential for actin cytoskeleton reorganization in hematopoietic cells. **Analysis of Incorrect Options:** * **Rett Syndrome:** This is an **X-linked dominant** disorder. It primarily affects females because it is typically lethal in utero for males. It is characterized by regression of motor and language skills and purposeful hand-wringing movements. * **Thalassemia:** This is a group of **autosomal recessive** hemoglobinopathies. Both Alpha and Beta thalassemias require inheritance of defective alleles from both parents to manifest the major disease state. * **Alkaptonuria:** This is a classic **autosomal recessive** metabolic disorder caused by a deficiency of homogentisate oxidase. It leads to the accumulation of homogentisic acid, causing dark urine and ochronosis. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic for X-linked Recessive:** "The **W**ise **G**iant **H**unter **D**ashed **B**riskly to **C**atch the **F**abry **L**ion" (**W**iskott-Aldrich, **G**6PD deficiency, **H**emophilia A/B, **D**uchenne/Becker MD, **B**ruton’s Agammaglobulinemia, **C**olor blindness, **F**abry disease, **L**esch-Nyhan). * **WAS Key Lab Finding:** Low IgM, high IgA, and high IgE levels, along with characteristically **small platelets** on a peripheral smear. * **Inheritance Pattern Tip:** Most enzyme deficiencies are Autosomal Recessive, while structural protein defects are often Autosomal Dominant. X-linked disorders are high-frequency topics in NEET-PG.

Question 356: A 24-year-old graduate student presents with complaints of severe muscle cramps and weakness with even mild exercise. Muscle biopsy demonstrates glycogen accumulation, but hepatic biopsy is unremarkable. Which of the following is the most likely diagnosis?

A. Pompe disease
B. Krabbe's disease
C. McArdle's disease (Correct Answer)
D. Niemann-Pick disease

Explanation: **Explanation:** The clinical presentation of exercise-induced muscle cramps and weakness, combined with glycogen accumulation isolated to the muscle (and not the liver), is the hallmark of **McArdle’s Disease (GSD Type V)**. **1. Why McArdle’s Disease is Correct:** McArdle’s disease is caused by a deficiency of **myophosphorylase** (muscle glycogen phosphorylase). This enzyme is essential for breaking down glycogen into glucose-1-phosphate in skeletal muscle. Because the liver isoform of the enzyme is coded by a different gene, hepatic function remains normal. Patients typically experience the "second wind" phenomenon, where symptoms improve after a few minutes of exercise as the body switches to using free fatty acids and blood glucose for energy. **2. Why the Other Options are Incorrect:** * **Pompe Disease (GSD Type II):** Caused by acid alpha-glucosidase deficiency. It involves systemic glycogen accumulation in lysosomes, primarily affecting the heart (cardiomegaly) and muscles, but it presents in infancy with severe hypotonia. * **Krabbe’s Disease:** A sphingolipidosis caused by galactocerebrosidase deficiency. It presents with neurological symptoms (demyelination, irritability, seizures) rather than exercise-induced muscle cramps. * **Niemann-Pick Disease:** A lysosomal storage disorder (sphingomyelinase deficiency) characterized by hepatosplenomegaly and neurodegeneration (Cherry-red spot on macula), not primary muscle pathology. **High-Yield Clinical Pearls for NEET-PG:** * **Ischemic Forearm Exercise Test:** In McArdle’s, this test shows a **failure of blood lactate to rise** (since glycogen cannot be converted to lactate) but a significant rise in ammonia. * **Myoglobinuria:** Severe exercise can lead to rhabdomyolysis and "burgundy-colored" urine. * **Mnemonic:** **M**cArdle = **M**uscle only; **v**ery (Type **V**) painful cramps.

Question 357: HbH disease is associated with which genetic abnormality?

A. Deletion of three alpha globin genes (Correct Answer)
B. Deletion of four alpha globin genes
C. Deletion of three beta globin genes
D. Deletion of four beta globin genes

Explanation: **Explanation:** **HbH disease** is a subtype of **Alpha-Thalassemia**, a condition characterized by a deficiency in the synthesis of alpha-globin chains. Normal human hemoglobin (HbA) consists of two alpha and two beta chains ($\alpha_2\beta_2$). Alpha-globin synthesis is controlled by **four genes** (two on each chromosome 16). 1. **Why Option A is correct:** HbH disease occurs when **three out of the four alpha-globin genes are deleted** ($--/-\alpha$). This results in a severe shortage of alpha chains. Consequently, the excess beta-globin chains (which are produced normally) aggregate to form tetramers ($\beta_4$), known as **Hemoglobin H (HbH)**. HbH has a high affinity for oxygen and is unstable, leading to chronic hemolytic anemia and the presence of "golf ball" inclusions (Heinz bodies) on supravital staining. 2. **Why other options are incorrect:** * **Option B:** Deletion of all **four** alpha genes ($--/--$) leads to **Hb Barts** ($\gamma_4$). This causes *Hydrops Fetalis*, which is usually fatal in utero. * **Options C & D:** Beta-thalassemia involves mutations (usually point mutations, not deletions) of the **two** beta-globin genes on chromosome 11. There is no clinical entity involving the deletion of three or four beta genes, as humans only possess two beta genes in total. **High-Yield Clinical Pearls for NEET-PG:** * **Genetics:** Alpha-thalassemia is primarily due to **gene deletions**, whereas Beta-thalassemia is primarily due to **point mutations**. * **Hb Barts:** Tetramer of four gamma chains ($\gamma_4$); seen in 4-gene deletion. * **HbH Inclusions:** Visible on **Brilliant Cresyl Blue** staining as "golf ball" or "pea-in-a-pod" appearance. * **Classification:** 1 gene deletion = Silent carrier; 2 genes = Alpha-thalassemia trait (mild anemia); 3 genes = HbH disease; 4 genes = Hydrops Fetalis.

Question 358: SnRNA mutation is associated with which syndrome?

A. Turner syndrome
B. Prader Willi syndrome (Correct Answer)
C. Klinefelter syndrome
D. Patau syndrome

Explanation: **Explanation:** **Prader-Willi Syndrome (PWS)** is the correct answer because it is fundamentally linked to the loss of expression of paternal genes on chromosome **15q11-q13**. A critical component of this region is the **SNRPN gene**, which encodes the **Small Nuclear Ribonucleoprotein Polypeptide N**. This protein is essential for the formation of **snRNPs (snurps)**, which are the core components of the **spliceosome**. Mutations or deletions affecting these snRNAs disrupt the alternative splicing of pre-mRNA in the brain, particularly in the hypothalamus, leading to the clinical features of PWS. **Analysis of Incorrect Options:** * **Turner Syndrome (45, XO):** A chromosomal numerical abnormality (monosomy) characterized by short stature and streak ovaries; it is not caused by snRNA mutations. * **Klinefelter Syndrome (47, XXY):** A sex chromosome aneuploidy resulting in primary hypogonadism and gynaecomastia; it involves an extra X chromosome, not splicing machinery. * **Patau Syndrome (Trisomy 13):** A trisomy characterized by midline defects (cleft lip/palate, holoprosencephaly) and polydactyly; it is a chromosomal duplication disorder. **High-Yield Clinical Pearls for NEET-PG:** * **Genetics of PWS:** Most commonly due to **Paternal Deletion** (70%) or **Maternal Uniparental Disomy** (25%). * **Clinical Triad:** Infantile hypotonia, hyperphagia leading to early-onset obesity, and hypogonadism. * **Splicing Connection:** Remember that **snRNAs (U1, U2, U4, U5, U6)** are rich in uridine and are vital for removing introns. PWS is one of the few classic genetic disorders directly linked to a defect in the splicing apparatus components. * **Diagnostic Tool:** DNA methylation analysis is the gold standard for diagnosis.

Question 359: Genetic deficiencies of NADPH oxidase cause which of the following conditions?

A. Mitochondrial myopathies
B. Chronic granulomatous diseases (Correct Answer)
C. Decreased ATP production
D. Lactic acidosis

Explanation: **Explanation:** **1. Why Chronic Granulomatous Disease (CGD) is Correct:** NADPH oxidase is a multi-subunit enzyme complex located in the membranes of phagosomes in neutrophils and macrophages. It is responsible for the **"Respiratory Burst,"** where it converts molecular oxygen ($O_2$) into superoxide radicals ($O_2^-$). These radicals are precursors to other reactive oxygen species (ROS) like hydrogen peroxide ($H_2O_2$) and hypochlorite ($HOCl$), which are essential for killing phagocytosed pathogens. A genetic deficiency in any subunit of NADPH oxidase (most commonly X-linked) leads to **Chronic Granulomatous Disease**. In CGD, phagocytes can ingest bacteria but cannot kill them, leading to recurrent infections and the formation of granulomas. **2. Why Incorrect Options are Wrong:** * **Mitochondrial Myopathies (A):** These are caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA encoding mitochondrial proteins, affecting the electron transport chain, not the phagocytic respiratory burst. * **Decreased ATP Production (C):** This is typically a result of defects in glycolysis, the TCA cycle, or Oxidative Phosphorylation (e.g., cyanide poisoning or complex deficiencies). NADPH oxidase uses NADPH to produce ROS; it does not produce ATP. * **Lactic Acidosis (D):** This occurs when there is a shift from aerobic to anaerobic metabolism (e.g., pyruvate dehydrogenase deficiency or severe hypoxia), leading to lactate accumulation. **3. High-Yield Clinical Pearls for NEET-PG:** * **Catalase-positive organisms:** Patients with CGD are specifically susceptible to organisms like *Staphylococcus aureus*, *Aspergillus*, *Serratia marcescens*, and *Nocardia*. These bacteria neutralize their own $H_2O_2$, leaving the CGD-affected neutrophil with no ROS to kill them. * **Diagnostic Test:** The **Nitroblue Tetrazolium (NBT) dye test** (remains colorless/yellow in CGD; turns blue in normal cells) or the more modern **Dihydrorhodamine (DHR) flow cytometry** test. * **Inheritance:** Most common form is **X-linked recessive** (CYBB gene mutation).

Question 360: Which of the following is a GM2 gangliosidosis?

A. Sandhoff's disease (Correct Answer)
B. Niemann-Pick disease
C. Gaucher's disease
D. Fabry's disease

Explanation: ### Explanation **GM2 Gangliosidoses** are a group of lysosomal storage disorders caused by the inability to degrade GM2 gangliosides. This occurs due to a deficiency in the enzyme **Hexosaminidase** or its activator protein. **1. Why Sandhoff’s Disease is Correct:** Sandhoff’s disease is caused by a deficiency in **Hexosaminidase A and B** (due to a mutation in the *HEXB* gene). This leads to the massive accumulation of GM2 gangliosides and globosides in the brain and other organs. It is clinically similar to Tay-Sachs disease (which is also a GM2 gangliosidosis) but often involves visceral organomegaly. **2. Why the Other Options are Incorrect:** * **Niemann-Pick Disease:** This is a **Sphingomyelinosis** caused by a deficiency of the enzyme **Sphingomyelinase**, leading to the accumulation of sphingomyelin. * **Gaucher’s Disease:** This is a **Glucosylceramide lipidosis** caused by a deficiency of **$\beta$-Glucosidase** (Glucocerebrosidase), leading to the accumulation of glucocerebroside. * **Fabry’s Disease:** This is an **X-linked** glycosphingolipidosis caused by a deficiency of **$\alpha$-Galactosidase A**, leading to the accumulation of ceramide trihexoside. **3. High-Yield Clinical Pearls for NEET-PG:** * **Tay-Sachs vs. Sandhoff:** Both present with a **Cherry-red spot** on the macula and progressive neurodegeneration. However, Sandhoff’s disease may present with **hepatosplenomegaly**, whereas Tay-Sachs does not. * **Enzyme mnemonic:** * Tay-Sachs = Hexosaminidase **A** (Missing **A**lpha subunit). * Sandhoff = Hexosaminidase **A & B** (Missing **B**eta subunit). * **Histology:** Look for "onion-skin" lysosomes in electron microscopy for GM2 gangliosidoses.

Practice by Chapter

Single Gene Disorders

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Biochemical Diagnosis of Genetic Disorders

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Inborn Errors of Metabolism

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Lysosomal Storage Diseases

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Glycogen Storage Diseases

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Disorders of Lipoprotein Metabolism

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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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