Genetic Disorders and Biochemical Pathology Practice Questions

Q: Which of the following gene mutations occurs in cleidocranial dysplasia?

CBFA1 gene. **Explanation:** **Cleidocranial Dysplasia (CCD)** is an autosomal dominant skeletal disorder primarily characterized by defective intramembranous and endochondral ossification. **1. Why CBFA1 is Correct:** The correct answer is **CBFA1** (Core-Binding Factor Alpha 1), now more commonly known as **RUNX2** (Runt-related transcription factor 2). This gene, located on chromosome 6p21, encodes a transcription factor essential for **osteoblast differentiation**. It acts as a "master switch" for bone formation. Mutations lead to a failure in the maturation of precursor cells into osteoblasts, resulting in the classic skeletal and dental abnormalities seen in CCD. **2. Why Other Options are Incorrect:** * **CDFA1:** This is a distractor and not a recognized gene associated with skeletal dysplasias. * **CBFA2:** Also known as **RUNX1**, this gene is primarily involved in hematopoiesis (blood cell formation). Mutations in CBFA2 are associated with Acute Myeloid Leukemia (AML) and familial platelet disorders, not skeletal morphogenesis. **3. High-Yield Clinical Pearls for NEET-PG:** * **Clinical Triad:** 1. **Aplasia/Hypoplasia of Clavicles:** Patients can often bring their shoulders together in the midline. 2. **Delayed Closure of Fontanelles:** Resulting in a large head with frontal bossing and open skull sutures (Wormian bones). 3. **Dental Abnormalities:** Presence of multiple **supernumerary teeth**, delayed eruption of permanent teeth, and a high arched palate. * **Inheritance:** Autosomal Dominant. * **Stature:** Patients usually have moderately short stature but normal intelligence.

Q: Which of the following is an autosomal dominant disorder?

Neurofibromatosis. **Explanation:** **Neurofibromatosis (Option B)** is the correct answer. Both Type 1 (NF1) and Type 2 (NF2) are classic examples of **autosomal dominant** disorders. NF1 is caused by a mutation in the *NF1* gene on chromosome 17 (encoding neurofibromin), while NF2 involves the *NF2* gene on chromosome 22 (encoding merlin). These conditions exhibit high penetrance but variable expressivity, meaning clinical severity can vary significantly among affected individuals. **Analysis of Incorrect Options:** * **A. G6PD Deficiency:** This is an **X-linked recessive** disorder. It is the most common enzyme deficiency worldwide, leading to episodic hemolytic anemia under oxidative stress (e.g., fava beans, primaquine). * **C. Hirschsprung's Disease:** This is primarily a **polygenic/multifactorial** disorder, though it can sometimes be associated with specific genetic syndromes (like Down syndrome) or mutations in the *RET* proto-oncogene. It does not follow a simple autosomal dominant inheritance pattern. * **D. Vitamin D Resistant Rickets (Hereditary Hypophosphatemic Rickets):** This is the classic example of an **X-linked dominant** disorder. It is characterized by renal phosphate wasting and is one of the few X-linked dominant conditions frequently tested in exams. **High-Yield Clinical Pearls for NEET-PG:** * **NF1 Clinical Triad:** Café-au-lait spots, Lisch nodules (iris hamartomas), and neurofibromas. * **Mnemonic for Autosomal Dominant Disorders:** "Very Powerful DOMINANT" (Von Willebrand, Polycystic Kidney Disease, Dystrophia Myotonica, Osteogenesis Imperfecta, Marfan, Intermittent Porphyria, **Neurofibromatosis**, Achondroplasia, Noonan, Tuberous Sclerosis). * **Genetic Concept:** NF1 has one of the highest mutation rates in the human genome; approximately 50% of cases arise from *de novo* mutations.

Q: Karyotyping is useful in the diagnosis of?

Chromosomal abnormalities. **Explanation:** **Karyotyping** is a cytogenetic technique used to examine the complete set of chromosomes in a cell. It involves arresting cells in **metaphase** (using colchicine), staining them (usually G-banding), and arranging them in a systematic order. **1. Why the correct answer is right:** Karyotyping is specifically designed to detect **Chromosomal Abnormalities**. These include: * **Numerical abnormalities (Aneuploidy):** Such as Trisomy 21 (Down Syndrome), 45,X (Turner Syndrome), or 47,XXY (Klinefelter Syndrome). * **Structural abnormalities:** Large-scale changes visible under a light microscope, such as translocations (e.g., Philadelphia chromosome t(9;22)), large deletions, or inversions. **2. Why the incorrect options are wrong:** * **Autosomal Recessive (A) and X-linked Recessive (C) disorders:** These are typically **single-gene (point) mutations** (e.g., Sickle cell anemia, Hemophilia). Karyotyping lacks the resolution to see changes at the DNA sequence level; these require molecular techniques like PCR or DNA sequencing. * **Biochemical abnormalities (D):** These refer to metabolic derangements (e.g., Phenylketonuria). These are diagnosed via metabolite assays (HPLC, Tandem Mass Spectrometry) or enzyme activity levels, not by looking at chromosomes. **Clinical Pearls for NEET-PG:** * **Resolution:** Standard karyotyping can detect changes larger than **5-10 Mb**. For smaller "microdeletions" (e.g., DiGeorge Syndrome), **FISH** (Fluorescence In Situ Hybridization) is the investigation of choice. * **Sample:** Peripheral blood (T-lymphocytes) is the most common sample; **Phytohemagglutinin** is added to stimulate mitosis. * **Prenatal diagnosis:** Karyotyping is performed on samples from Amniocentesis or Chorionic Villus Sampling (CVS).

Q: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is due to deficiency of which enzyme?

Ornithine translocase. **Explanation:** **HHH Syndrome** is an autosomal recessive urea cycle disorder caused by a mutation in the **SLC25A15 gene**, which encodes the **Ornithine Translocase (ORNT1)** protein. 1. **Why Ornithine Translocase is correct:** The urea cycle occurs in both the mitochondria and the cytosol. Ornithine is produced in the cytosol but must be transported into the mitochondria to react with carbamoyl phosphate (via OTC). Ornithine translocase is the specific transporter responsible for this shuttle. When deficient, ornithine cannot enter the mitochondria, leading to: * **Hyperornithinemia:** Accumulation of ornithine in the cytosol/blood. * **Hyperammonemia:** The urea cycle is "stalled" due to lack of mitochondrial ornithine, leading to ammonia buildup. * **Homocitrullinuria:** In the absence of ornithine, the enzyme OTC uses **lysine** as an alternative substrate, producing homocitrulline, which is excreted in the urine. 2. **Why the other options are incorrect:** * **Ornithine permease:** This is a general term for transport proteins in bacteria/lower organisms; it is not the specific human transporter involved in HHH syndrome. * **Ornithine decarboxylase:** This enzyme converts ornithine to putrescine (polyamine synthesis); its deficiency does not cause the HHH triad. * **Ornithine transcarbamoylase (OTC):** Deficiency causes the most common urea cycle disorder (X-linked), characterized by hyperammonemia and orotic aciduria, but *not* hyperornithinemia. **High-Yield Clinical Pearls for NEET-PG:** * **The Triad:** Hyperornithinemia, Hyperammonemia, and Homocitrullinuria. * **Genetics:** Autosomal Recessive (unlike OTC deficiency, which is X-linked). * **Clinical Presentation:** Post-prandial irritability, lethargy, seizures, and characteristic **spastic paraplegia** in chronic cases. * **Diagnosis:** Elevated plasma ornithine and urinary homocitrulline.

Q: Which amino acids are excreted in the urine in cystinosis?

All of the above. **Explanation:** The correct answer is **D. All of the above**. To understand this, it is crucial to distinguish between **Cystinuria** and **Cystinosis**, as they are frequently confused in exams. 1. **Cystinosis:** This is a lysosomal storage disorder caused by a defect in the **CTNS gene**, which encodes **cystinosin**, a lysosomal cystine transporter. This leads to the accumulation of cystine crystals within lysosomes across various organs. In the kidneys, this accumulation causes generalized proximal tubular damage, known as **Renal Fanconi Syndrome**. Because the entire proximal tubule is dysfunctional, there is a failure to reabsorb *all* amino acids (generalized aminoaciduria), glucose, phosphates, and bicarbonates. Therefore, cystine, ornithine, arginine, and lysine (the COAL group) are all excreted, along with many others. 2. **Cystinuria (The "COAL" mnemonic):** This is a specific transport defect in the proximal tubule and small intestine involving only the dibasic amino acids: **C**ystine, **O**rnithine, **A**rginine, and **L**ysine. While "COAL" excretion is the hallmark of Cystinuria, these same amino acids are also excreted in Cystinosis due to the broader Fanconi Syndrome. **Clinical Pearls for NEET-PG:** * **Cystinosis:** Characterized by growth retardation, photophobia (due to corneal crystals), and early-onset renal failure. It is the most common cause of Fanconi Syndrome in children. * **Cystinuria:** Presents with recurrent **hexagonal cystine stones** (calculi). Diagnosis is via the **Cyanide-Nitroprusside test** (purple color). * **Treatment:** Cystinosis is treated with **Cysteamine** (depletes lysosomal cystine); Cystinuria is managed with hydration, urinary alkalinization, and Penicillamine.

Q: Cat eye syndrome is associated with which chromosomal abnormality?

Trisomy 22. **Explanation:** **Cat Eye Syndrome (Schmid-Fraccaro Syndrome)** is a rare chromosomal disorder caused by the presence of an extra chromosome, specifically a **partial trisomy or tetrasomy of the short arm (p) and a small section of the long arm (q) of chromosome 22**. While the question simplifies this as "Trisomy 22," it is technically a small supernumerary marker chromosome (sSMC) derived from chromosome 22. The name "Cat Eye" is derived from the characteristic **coloboma of the iris** (a vertical gap in the colored part of the eye), which resembles a feline pupil. However, this feature is only present in about 50% of cases. **Analysis of Incorrect Options:** * **A. Trisomy 13 (Patau Syndrome):** Characterized by the triad of microphthalmia, cleft lip/palate, and polydactyly. It is much more severe and often fatal in infancy. * **B. Trisomy 18 (Edwards Syndrome):** Presents with micrognathia, low-set ears, clenched fists with overlapping fingers, and rocker-bottom feet. * **C. Trisomy 21 (Down Syndrome):** The most common autosomal trisomy, characterized by intellectual disability, flat facial profile, Simian crease, and Brushfield spots. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Triad of Cat Eye Syndrome:** Iris coloboma, anal atresia (with fistula), and preauricular pits/tags. * **Cardiac defects:** Total anomalous pulmonary venous connection (TAPVC) is frequently associated. * **Cytogenetics:** Look for the "inverted duplicated chromosome 22" in karyotyping. * **Full Trisomy 22:** Unlike partial trisomy 22 (Cat Eye), full trisomy 22 is usually incompatible with life and is a common cause of first-trimester spontaneous abortions.

Q: Which disorder is associated with convulsions, cataract, and mental retardation?

Galactosaemia. **Explanation:** **Galactosaemia** (specifically Classic Galactosemia due to GALT deficiency) is the correct answer because it presents with a classic triad of symptoms: **cataracts, liver dysfunction, and intellectual disability.** The accumulation of **galactose-1-phosphate** is toxic to the liver, brain, and kidneys. The formation of **galactitol** via aldose reductase in the lens leads to osmotic swelling and cataracts. **Convulsions** occur due to acute hypoglycemia (as galactose-1-phosphate inhibits phosphoglucomutase and glucose-6-phosphatase) and hyperammonemia from liver failure. **Why other options are incorrect:** * **Phenylketonuria (PKU):** Characterized by intellectual disability, "mousy" body odor, and hypopigmentation. While it causes mental retardation and seizures, it is **not** associated with cataracts. * **Tyrosinemia (Type I):** Primarily presents with cabbage-like odor, liver failure, renal tubular acidosis (Fanconi syndrome), and rickets. It does not typically cause cataracts. * **Maple Syrup Urine Disease (MSUD):** Caused by a deficiency in Branched-Chain Alpha-Keto Acid Dehydrogenase. It presents with a "burnt sugar" urine odor, encephalopathy, and dystonia, but not cataracts. **High-Yield Clinical Pearls for NEET-PG:** * **Enzyme Deficiency:** Classic Galactosemia is due to **Galactose-1-phosphate uridyltransferase (GALT)** deficiency. * **Cataract Type:** Described as **"Oil Drop" cataracts.** * **Infection Risk:** Patients have a significantly increased risk of **E. coli neonatal sepsis.** * **Diagnosis:** Reducing substances in urine (clinitest positive) but glucose oxidase test (dipstick) negative. * **Management:** Immediate withdrawal of lactose/galactose from the diet (soy-based formula).

Q: McArdle's disease causes muscle cramps and muscle fatigue with increased muscle glycogen. Which of the following enzymes is deficient?

Muscle phosphorylase. **Explanation:** **McArdle’s Disease (Glycogen Storage Disease Type V)** is caused by a deficiency of **Muscle Phosphorylase** (myophosphorylase). This enzyme is responsible for the rate-limiting step of glycogenolysis in skeletal muscle, breaking down glycogen into glucose-1-phosphate. Without it, muscles cannot mobilize glucose during strenuous exercise, leading to the characteristic clinical triad of muscle cramps, exercise intolerance, and increased muscle glycogen stores. **Analysis of Options:** * **Muscle Phosphorylase (Correct):** Deficiency prevents glycogen breakdown in muscles. A hallmark finding is the **failure of blood lactate to rise** after ischemic exercise, as glycogen cannot be converted to lactate. * **Hepatic Hexokinase:** This enzyme is involved in glucose phosphorylation in the liver. Its deficiency would affect glycolysis, not glycogen storage, and would not present with muscle-specific symptoms. * **Muscle Glycogen Synthetase:** Deficiency of this enzyme (GSD Type 0b) would lead to a *decrease* in glycogen levels (hypoglycemia/fatigue), whereas McArdle’s presents with *increased* glycogen. * **Muscle Hexokinase:** While hexokinase is vital for glucose entry into glycolysis, its deficiency does not lead to the massive accumulation of glycogen seen in GSDs. **High-Yield Clinical Pearls for NEET-PG:** * **"Second Wind" Phenomenon:** Patients often experience improved exercise tolerance after a few minutes of activity once the body switches to using free fatty acids and blood glucose. * **Myoglobinuria:** Intense exercise can lead to rhabdomyolysis, resulting in "burgundy-colored" urine (myoglobinuria) and potential renal failure. * **Diagnosis:** Ischemic forearm exercise test (flat lactate curve) and muscle biopsy showing subsarcolemmal glycogen deposits.

Q: Ehlers-Danlos syndrome, characterized by hypermobile joints and skin abnormalities, is due to:

Abnormality in a gene for procollagen. **Explanation:** **Ehlers-Danlos Syndrome (EDS)** is a heterogeneous group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. **Why Option A is Correct:** The primary molecular defect in most types of EDS involves mutations in the **genes encoding for Type I, III, or V procollagen** (e.g., *COL5A1, COL3A1*). These mutations lead to the production of structurally abnormal procollagen chains, which interfere with the normal assembly and cross-linking of collagen fibrils, resulting in weakened connective tissues. **Why the Other Options are Incorrect:** * **Option B (Lysyl Oxidase):** Deficiency of this copper-dependent enzyme leads to **Menkes Disease** or **Lathyrism**. It is responsible for the final cross-linking step of collagen/elastin, not the primary defect in classic EDS. * **Option C (Prolyl Hydroxylase):** This enzyme requires Vitamin C as a cofactor. Its deficiency results in **Scurvy**, characterized by bleeding gums and poor wound healing due to impaired collagen hydroxylation. * **Option D (Lysyl Hydroxylase):** While a deficiency of this enzyme causes **EDS Type VI (Kyphoscoliotic type)**, it is a specific subtype. Option A is the broader and more accurate answer for EDS as a general clinical entity, as most cases involve structural gene mutations rather than enzyme deficiencies. **High-Yield NEET-PG Pearls:** * **EDS Type IV (Vascular Type):** Due to a defect in **Type III Collagen**; it is the most severe form, associated with arterial or organ rupture. * **EDS Type V (Classic Type):** Due to a defect in **Type V Collagen**. * **Key Clinical Sign:** "Cigarette paper" or "Papyraceous" scars are characteristic of EDS. * **Collagen Synthesis:** Remember that hydroxylation occurs in the ER (requires Vit C), while cross-linking occurs extracellularly (requires Copper).

Question 1

Which of the following gene mutations occurs in cleidocranial dysplasia?

Accepted Answer

CBFA1 gene

Answer

CDFA1 gene

Answer

CBFA2 gene

Answer

None

Question 2

Which of the following is an autosomal dominant disorder?

Accepted Answer

Neurofibromatosis

Answer

G6PD deficiency

Answer

Hirschsprung's disease

Answer

Vitamin D resistant rickets

Question 3

Karyotyping is useful in the diagnosis of?

Accepted Answer

Chromosomal abnormalities

Answer

Autosomal recessive disorders

Answer

X-linked recessive disorders

Answer

Biochemical abnormalities

Question 4

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is due to deficiency of which enzyme?

Accepted Answer

Ornithine translocase

Answer

Ornithine permease

Answer

Ornithine decarboxylase

Answer

Ornithine transcarbamoylase

Question 5

Which amino acids are excreted in the urine in cystinosis?

Accepted Answer

All of the above

Answer

Cystine

Answer

Ornithine

Answer

Arginine

Question 6

Cat eye syndrome is associated with which chromosomal abnormality?

Accepted Answer

Trisomy 22

Answer

Trisomy 13

Answer

Trisomy 18

Answer

Trisomy 21

Question 7

Which disorder is associated with convulsions, cataract, and mental retardation?

Accepted Answer

Galactosaemia

Answer

Phenylketonuria

Answer

Tyrosinemia

Answer

Maple syrup disease

Question 8

McArdle's disease causes muscle cramps and muscle fatigue with increased muscle glycogen. Which of the following enzymes is deficient?

Accepted Answer

Muscle phosphorylase

Answer

Hepatic hexokinase

Answer

Muscle glycogen synthetase

Answer

Muscle hexokinase

Question 9

Ehlers-Danlos syndrome, characterized by hypermobile joints and skin abnormalities, is due to:

Accepted Answer

Abnormality in a gene for procollagen

Answer

Deficiency of lysyl oxidase

Answer

Deficiency of prolyl hydroxylase

Answer

Deficiency of lysyl hydroxylase

Question 10

Mental retardation is not a feature in which of the following aminoacidurias?

Accepted Answer

Albinism

Answer

Phenylketonuria

Answer

Homocystinuria

Answer

Maple syrup urine disease

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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