Genetics and Disease — MCQs

A 15-year-old boy presents with tremors, difficulty in speech, and behavioral changes. On examination, he has hepatomegaly and a golden-brown ring at the limbus of the cornea (Kayser-Fleischer ring). Wilson's disease is suspected. Which of the following is the best investigation to support the diagnosis?

Q200

Which of the following genetic mutations is most commonly associated with familial cases of Amyotrophic Lateral Sclerosis (ALS)?

Genetics and Disease Indian Medical PG Practice Questions and MCQs

Question 191: McArdle's syndrome is due to which of the following deficiencies?

A. Deficiency of glucose-6-phosphatase (Correct Answer)
B. Absence of muscle phosphorylase
C. Deficiency of liver phosphorylase
D. Deficiency of liver phosphorylase kinase

Explanation: Detailed Analysis: McArdle’s disease (GSD Type V) is an autosomal recessive metabolic disorder characterized by the **absence of muscle phosphorylase** (myophosphorylase) [1]. This enzyme is essential for glycogenolysis in skeletal muscle; its deficiency prevents the breakdown of muscle glycogen into glucose-1-phosphate, leading to an energy crisis during the initial stages of exercise [1]. **Analysis of Options:** * **Option B (Correct):** McArdle’s disease is specifically caused by a deficiency of **muscle phosphorylase**. This leads to exercise intolerance, muscle cramps, and myoglobinuria [2]. * **Option A (Incorrect):** Deficiency of **glucose-6-phosphatase** causes **Von Gierke’s disease (GSD Type I)**, characterized by severe fasting hypoglycemia, hepatomegaly, and hyperuricemia [1]. * **Option C (Incorrect):** Deficiency of **liver phosphorylase** causes **Hers disease (GSD Type VI)**, which presents with hepatomegaly and mild hypoglycemia. * **Option D (Incorrect):** Deficiency of **liver phosphorylase kinase** causes **GSD Type IX**, which is clinically similar to Hers disease. **Clinical Pearls for NEET-PG:** 1. **Second Wind Phenomenon:** A hallmark of McArdle’s where patients experience relief from fatigue/cramps after a few minutes of exercise as the body switches to using free fatty acids and blood glucose. 2. **Ischemic Forearm Exercise Test:** Classically shows a **failure of blood lactate to rise** with a concomitant rise in ammonia levels. 3. **Burgundy-colored urine:** Post-exercise myoglobinuria can lead to acute renal failure. 4. **Biopsy:** Shows subsarcolemmal deposits of glycogen.

Question 192: Which of the following conditions is NOT caused by the overexpression of a trinucleotide repeat?

A. Alzheimer's disease (Correct Answer)
B. Fragile X syndrome
C. Huntington disease
D. Spinocerebellar ataxia Type 2

Explanation: **Explanation:** The correct answer is **Alzheimer’s disease**. This condition is a neurodegenerative disorder primarily associated with the accumulation of amyloid-beta plaques and tau tangles [1]. Its genetic basis involves mutations in the **APP, PSEN1, and PSEN2** genes (early-onset) or the **APOE-ε4** allele (late-onset), rather than trinucleotide repeat expansions. **Analysis of Options:** * **Fragile X Syndrome:** Caused by a **CGG** repeat expansion in the *FMR1* gene. It is the most common inherited cause of intellectual disability. * **Huntington Disease:** An autosomal dominant disorder caused by **CAG** repeats in the *HTT* gene on chromosome 4 [2]. It exhibits "anticipation," where the disease manifests earlier in successive generations. * **Spinocerebellar Ataxia (SCA) Type 2:** Part of a group of autosomal dominant ataxias caused by **CAG** repeats (polyglutamine diseases) affecting the *ATXN2* gene [2]. **NEET-PG High-Yield Pearls:** 1. **Anticipation:** This phenomenon (earlier onset/increased severity in offspring) is a hallmark of trinucleotide repeat disorders due to further expansion during gametogenesis. 2. **Repeat Locations:** * **CAG (Polyglutamine):** Huntington’s, SCA, Spinal Bulbar Muscular Ataxia (Kennedy disease). * **CGG:** Fragile X (Non-coding region). * **GAA:** Friedreich’s Ataxia (Intronic). * **CTG:** Myotonic Dystrophy. 3. **Alzheimer’s Association:** Down Syndrome patients have an increased risk of Alzheimer’s because the *APP* gene is located on **Chromosome 21**.

Question 193: If both parents are sickle cell anemia patients, what is the likelihood of their offspring having the disease?

A. 10%
B. 25%
C. 50%
D. 100% (Correct Answer)

Explanation: **Explanation:** **1. Why the Correct Answer is Right:** Sickle Cell Anemia (SCA) is an **autosomal recessive** disorder caused by a point mutation in the HBB gene on chromosome 11. For an individual to manifest the disease (SCA), they must possess two copies of the mutated hemoglobin S (HbS) allele (genotype: **ss**) [1]. In this scenario, both parents are patients (not just carriers), meaning both have the genotype **ss**. According to Mendelian inheritance, a cross between two homozygous recessive parents (**ss × ss**) will result in offspring that are all **ss**. Therefore, there is a **100% probability** that every child will inherit the disease. **2. Why the Incorrect Options are Wrong:** * **Option A (10%):** This value does not correspond to any standard Mendelian inheritance pattern for a single-gene disorder. * **Option B (25%):** This is the risk of having an affected child when **both parents are carriers** (Sickle Cell Trait, genotype **As**). * **Option C (50%):** This is the risk when **one parent is a patient (ss)** and the **other is a carrier (As)**. **3. NEET-PG Clinical Pearls & High-Yield Facts:** * **Molecular Basis:** Glutamic acid is replaced by **Valine** at the 6th position of the beta-globin chain. * **Sickling Trigger:** Occurs under conditions of hypoxia, acidosis, and dehydration. * **Protective Effect:** Heterozygotes (Sickle Cell Trait) have a selective advantage against *Plasmodium falciparum* malaria. * **Diagnosis:** **High-Performance Liquid Chromatography (HPLC)** is the gold standard; Solubility tests and peripheral smears (sickle cells, Howell-Jolly bodies) are screening tools [1]. * **Management:** Hydroxyurea is used to increase **HbF** levels, which inhibits the polymerization of HbS [1].

Question 194: In Von Hippel-Lindau Syndrome, retinal vascular tumors are often associated with intracranial hemangioblastomas. Which one of the following regions is associated with such vascular abnormalities in this syndrome?

A. Optic radiation
B. Optic tract
C. Cerebellum (Correct Answer)
D. Pulvinar

Explanation: **Explanation:** **Von Hippel-Lindau (VHL) Syndrome** is an autosomal dominant multisystem disorder caused by a mutation in the **VHL gene on chromosome 3p25**. This gene normally acts as a tumor suppressor by degrading Hypoxia-Inducible Factor (HIF). Its loss leads to the overproduction of angiogenic factors like VEGF, resulting in highly vascular tumors. **Why the Correct Answer is Right:** The hallmark CNS lesion in VHL is the **hemangioblastoma**. These are benign but highly vascular tumors that most commonly occur in the **Cerebellum (60-80%)**, followed by the spinal cord and brainstem. In this question, the association of retinal angiomas (von Hippel tumors) with cerebellar hemangioblastomas (Lindau tumors) defines the classic presentation of the syndrome. **Why the Incorrect Options are Wrong:** * **Optic radiation, Optic tract, and Pulvinar:** While VHL affects the visual system via retinal hemangioblastomas, it does not typically cause vascular tumors in the retro-chiasmal pathways (tracts/radiations) or the thalamic nuclei (pulvinar). Hemangioblastomas in VHL have a predilection for the **infratentorial compartment** (posterior fossa) rather than the supratentorial white matter or deep gray matter. **High-Yield Clinical Pearls for NEET-PG:** * **VHL Gene:** Chromosome **3**. * **Classic Triad:** Retinal hemangioblastomas, Cerebellar hemangioblastomas, and Renal Cell Carcinoma (RCC). * **Associated Findings:** Pheochromocytoma (Type 2 VHL), Pancreatic cysts/NETs, and Endolymphatic sac tumors (causing hearing loss). * **RCC Type:** Clear cell variant (often bilateral and multifocal). * **Most common cause of death:** Renal Cell Carcinoma or complications from CNS hemangioblastomas.

Question 195: Which of the following is NOT a characteristic of Xeroderma Pigmentosum?

A. It is an autosomal recessive disorder. (Correct Answer)
B. It is caused by defective DNA repair.
C. It is associated with an increased risk of squamous cell carcinoma.
D. Exposure to ultraviolet radiation can lead to the formation of thymine dimers.

Explanation: The question asks for the statement that is **NOT** a characteristic of Xeroderma Pigmentosum (XP). However, based on medical facts, **Option A is actually a true characteristic** of the disease. In the context of this question, there appears to be a technical error in the provided key, as all four options (A, B, C, and D) are scientifically correct descriptions of XP. ### **Medical Explanation** 1. **Why Option A is a characteristic:** Xeroderma Pigmentosum is a classic **autosomal recessive** genetic disorder [1]. It occurs when a child inherits two mutated copies of the XP genes (XPA through XPG). 2. **Why Option B is a characteristic:** The fundamental pathology is a **defect in Nucleotide Excision Repair (NER)** [1]. This system is responsible for "cutting out" DNA segments damaged by environmental factors. 3. **Why Option C is a characteristic:** Due to the inability to repair DNA, patients have a >1000-fold increased risk of cutaneous malignancies, including **Squamous Cell Carcinoma (SCC)**, Basal Cell Carcinoma (BCC), and Melanoma. 4. **Why Option D is a characteristic:** UV radiation (specifically UV-B) causes the formation of **pyrimidine dimers (thymine dimers)**. In healthy individuals, NER fixes these; in XP patients, they persist, leading to mutations and carcinogenesis. ### **High-Yield Clinical Pearls for NEET-PG** * **Early Sign:** Severe "sunburn" after minimal sun exposure and extensive freckling (lentigines) before age 2. * **Neurological Involvement:** About 20-30% of patients (e.g., De Sanctis-Cacchione syndrome) show progressive neurodegeneration and sensorineural deafness. * **Ocular Findings:** Photophobia, keratitis, and corneal opacification are common. * **Management:** Strict UV protection (sunscreen, protective clothing) and regular dermatological surveillance.

Question 196: In a family, the father has widely spaced eyes, increased facial hair, and deafness. One of the three children has deafness with similar facial features. The mother is normal. Which one of the following is the most likely pattern of inheritance in this case?

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

Explanation: **Explanation:** The clinical presentation described—widely spaced eyes (telecanthus), synophrys (increased facial hair/unibrow), and sensorineural deafness—is characteristic of **Waardenburg Syndrome**. **1. Why Autosomal Dominant (AD) is correct:** In this scenario, the condition is transmitted directly from an affected father to his child. This represents **vertical transmission** (seen in every generation). Since the mother is normal and the trait appears in the offspring, it indicates that a single copy of the mutant allele from the father is sufficient to cause the phenotype. This is the hallmark of Autosomal Dominant inheritance. **2. Why other options are incorrect:** * **Autosomal Recessive (AR):** This typically presents with **horizontal transmission** (skipped generations). For a child to be affected, both parents must usually be carriers. If the mother is "normal" (not a carrier), an AR condition would not manifest in the child. * **X-linked Dominant (XLD):** While an affected father can pass an XLD trait to his daughters, he **cannot** pass it to his sons (as he gives them a Y chromosome). The question mentions "one of three children" without specifying gender; however, AD is the more common and classic fit for Waardenburg Syndrome (Type 1 and 2). * **X-linked Recessive (XLR):** An affected father would pass the gene to all daughters (making them carriers) but none of his children would typically be affected unless the mother was also a carrier. **Clinical Pearls for NEET-PG:** * **Waardenburg Syndrome:** Look for "White forelock" (poliosis), heterochromia iridis (different colored eyes), and sensorineural hearing loss. * **High-Yield Rule:** Vertical transmission + Male-to-Male transmission = **Autosomal Dominant**. * **Mnemonic:** Most structural protein defects are AD; most enzyme deficiencies are AR.

Question 197: A teenage boy, who was previously raised as a girl, presents with primary amenorrhea and lack of secondary sexual characteristics. On examination, he has tall stature, small testes, and gynecomastia. Which of the following is the most likely genotype?

A. 47,XYY
B. 47,XXY (Correct Answer)
C. 45,X
D. 46,XX

Explanation: ***Correct: 47,XXY (Klinefelter Syndrome)*** - This patient presents with **classic features of Klinefelter syndrome**: tall stature, small firm testes, gynecomastia, and hypogonadism [1]. - The **47,XXY karyotype** results from meiotic nondisjunction leading to an extra X chromosome. - **Hypogonadism** causes decreased testosterone, leading to lack of secondary sexual characteristics and increased FSH/LH [1]. - Patients typically have **eunuchoid body proportions** (tall stature with long limbs) due to delayed epiphyseal closure [1]. - The presence of **gynecomastia** is due to relative estrogen excess compared to testosterone [1]. - Primary amenorrhea mentioned here likely refers to the lack of pubertal development (developmental delay). *Incorrect: 47,XYY (Supermale Syndrome)* - These individuals are **tall males with normal virilization** and normal-sized testes - No gynecomastia or hypogonadism - Often associated with learning difficulties but normal sexual development *Incorrect: 45,X (Turner Syndrome)* - Presents in **phenotypic females** with **short stature** (not tall) [2]. - Features include webbed neck, shield chest, coarctation of aorta - Primary amenorrhea present but patient would be raised as female throughout - Does not explain male phenotype or gynecomastia in this case *Incorrect: 46,XX (Normal Female Karyotype)* - Normal female karyotype would not explain **male phenotype** with testes - Does not account for gynecomastia or the clinical presentation described

Question 198: A mutation in the SOD1 gene is most commonly associated with which of the following conditions?

A. Parkinson's disease
B. Multiple sclerosis
C. Huntington's disease
D. Amyotrophic lateral sclerosis (ALS) (Correct Answer)

Explanation: ***Amyotrophic lateral sclerosis (ALS)*** - **SOD1 (Superoxide dismutase 1)** gene mutations are responsible for approximately **20% of familial ALS** cases and 1-2% of sporadic cases - SOD1 enzyme normally protects cells from oxidative damage by converting superoxide radicals to hydrogen peroxide - Mutations lead to **toxic gain of function** causing motor neuron degeneration, affecting both upper and lower motor neurons [1] - Clinical features include progressive muscle weakness, fasciculations, spasticity, and bulbar symptoms [1] - This is one of the **most well-established genetic associations** in neurodegenerative disease *Parkinson's disease* - Associated with mutations in **SNCA (α-synuclein), LRRK2, and Parkin** genes, not SOD1 - Characterized by dopaminergic neuron loss in substantia nigra - Presents with bradykinesia, rigidity, resting tremor, and postural instability *Multiple sclerosis* - An **autoimmune demyelinating disease** with complex genetic susceptibility involving HLA-DRB1 and other immune-related genes - Not linked to SOD1 mutations - Presents with relapsing-remitting neurological symptoms and white matter lesions *Huntington's disease* - Caused by **CAG trinucleotide repeat expansion** in the huntingtin (HTT) gene on chromosome 4 - Autosomal dominant inheritance with anticipation - Presents with chorea, cognitive decline, and psychiatric symptoms

Question 199: A 15-year-old boy presents with tremors, difficulty in speech, and behavioral changes. On examination, he has hepatomegaly and a golden-brown ring at the limbus of the cornea (Kayser-Fleischer ring). Wilson's disease is suspected. Which of the following is the best investigation to support the diagnosis?

A. Serum ceruloplasmin
B. Liver biopsy for copper estimation (Correct Answer)
C. Copper excretion in urine
D. Serum copper

Explanation: ***Liver biopsy for copper estimation*** - This is considered the **gold standard** diagnostic test for Wilson's disease, as it directly measures the pathologically increased copper accumulation in the liver - A hepatic copper concentration greater than **250 µg per gram** dry weight is generally diagnostic of Wilson's disease - **Important clinical context:** In this case, the presence of **Kayser-Fleischer rings with neurological symptoms** makes the diagnosis of Wilson's disease virtually certain [1]. In such scenarios, liver biopsy may **not be necessary** as the diagnosis can be confirmed with non-invasive investigations (ceruloplasmin + urinary copper) - Liver biopsy is primarily indicated when the diagnosis is **uncertain** or when non-invasive tests are inconclusive [2] - However, as the question asks for the "best investigation to support the diagnosis," liver biopsy remains the most **definitive** test, though not always the most **practical** first choice *Serum ceruloplasmin* - This is typically the **first-line investigation** for suspected Wilson's disease and is usually low (<20 mg/dL or <200 mg/L) - However, up to 10–20% of symptomatic patients may present with **normal serum ceruloplasmin** levels, particularly in children - Low ceruloplasmin levels are also seen in other conditions, such as **protein-losing states**, severe malnutrition, or other copper metabolism disorders, limiting its specificity - In the presence of KF rings, a low ceruloplasmin is highly supportive and often sufficient for diagnosis *Serum copper* - Total serum copper is often low because ceruloplasmin (the main copper-carrying protein) level is low, but this finding is **non-specific** - In the setting of **fulminant hepatic failure**, massive release of stored copper can occur, leading to paradoxically normal or even elevated serum copper levels [1] - Free (non-ceruloplasmin-bound) copper is elevated in Wilson's disease but is difficult to measure directly *Copper excretion in urine* - Elevated 24-hour urinary copper excretion (usually **>100 µg/day**) is a highly supportive finding, reflecting increased levels of non-ceruloplasmin-bound copper - Values **>1,000 µg/day** strongly suggest acute liver failure due to Wilson's disease - The reliability of this test can be hampered by **incomplete or inaccurate 24-hour urine collection**, making it less conclusive than direct liver copper measurement - This is an excellent non-invasive supportive test when KF rings are present

Question 200: Which of the following genetic mutations is most commonly associated with familial cases of Amyotrophic Lateral Sclerosis (ALS)?

A. HTT gene mutation
B. CFTR gene mutation
C. FMR1 gene mutation
D. SOD1 gene mutation (Correct Answer)

Explanation: ***SOD1 gene mutation***- Mutations in the **Superoxide Dismutase 1 (SOD1)** gene are historically significant and account for approximately 15–20% of all familial ALS cases.- The SOD1 protein is located in the cytoplasm and mitochondria, and mutations lead to toxic misfolding and aggregation, resulting in **motor neuron death**.*CFTR gene mutation*- The **CFTR (Cystic Fibrosis Transmembrane Conductance Regulator)** gene mutation is critically linked to the development of **Cystic Fibrosis**, a severe disorder of exocrine glands.- This mutation primarily affects chloride ion transport across epithelia, leading to highly viscous secretions, particularly in the airways and pancreas, not motor neuron disease.*HTT gene mutation*- Mutations involving the **HTT (Huntingtin)** gene, specifically expanded **CAG trinucleotide repeats**, cause **Huntington's disease**.- Huntington’s disease is characterized by progressive degeneration of the **striatum** and cortex, leading to movement abnormalities (*chorea*), cognitive decline, and psychiatric symptoms, distinct from ALS.*FMR1 gene mutation*- The **FMR1 (Fragile X Messenger Ribonucleoprotein 1)** gene is responsible for **Fragile X syndrome**, the most common inherited cause of intellectual disability.- The mutation involves expansion of the **CGG trinucleotide repeat**, typically leading to transcriptional silencing and symptoms like macroorchidism and behavioral issues, not primary motor neuron degeneration.

Practice by Chapter

Principles of Medical Genetics

Practice Questions

Genetic Testing and Counseling

Practice Questions

Single Gene Disorders

Practice Questions

Chromosomal Disorders

Practice Questions

Mitochondrial Diseases

Practice Questions

Pharmacogenomics

Practice Questions

Cancer Genetics

Practice Questions

Genetics of Common Diseases

Practice Questions

Epigenetics and Disease

Practice Questions

Genetic Basis of Developmental Disorders

Practice Questions

Ethical Issues in Medical Genetics

Practice Questions

Gene Therapy and Precision Medicine

Practice Questions

Want unlimited practice?

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

Start For Free