Genetic Disorders and Biochemical Pathology Practice Questions

Q: All are true about Fabry disease, EXCEPT:

Retinitis pigmentosa is well described in Fabry disease. **Explanation:** **Fabry disease** is a lysosomal storage disorder caused by the deficiency of the enzyme **$\alpha$-galactosidase A**, leading to the systemic accumulation of **globotriaosylceramide (ceramide trihexoside)**. 1. **Why Option C is the correct answer (The "EXCEPT"):** Retinitis pigmentosa is **not** a feature of Fabry disease. The characteristic ocular finding in Fabry disease is **Cornea Verticillata** (vortex keratopathy/whorl-like corneal opacities), which does not typically affect vision. Other ocular signs include posterior subcapsular cataracts and tortuous conjunctival vessels. Retinitis pigmentosa is more commonly associated with disorders like Refsum disease or Usher syndrome. 2. **Analysis of other options:** * **Option A:** Fabry disease is unique among sphingolipidoses (most are autosomal recessive) because it is an **X-linked recessive** disorder. * **Option B:** The accumulation of glycosphingolipids in the vascular endothelium leads to narrowing of the lumen, causing **premature atherosclerosis**, myocardial infarction, and stroke at a young age. * **Option D:** The primary substrate that accumulates in the lysosomes of nerves, kidneys, and blood vessels is **ceramide trihexoside** (also known as $Gb_3$). **High-Yield Clinical Pearls for NEET-PG:** * **Early Signs:** Episodic peripheral neuropathy (**acroparesthesia**—burning pain in hands/feet), **angiokeratomas** (dark red skin spots in bathing trunk distribution), and **hypohidrosis** (decreased sweating). * **Late Complications:** Progressive renal failure (leading cause of death) and hypertrophic cardiomyopathy. * **Diagnosis:** Low $\alpha$-galactosidase A activity in leukocytes; confirmed by genetic testing. * **Treatment:** Enzyme Replacement Therapy (ERT) with Agalsidase beta.

Q: Which treatment is contraindicated in hypophosphatasia?

Vitamin D. **Explanation:** **Hypophosphatasia (HPP)** is a rare genetic disorder caused by a loss-of-function mutation in the **ALPL gene**, which encodes **Tissue-Nonspecific Alkaline Phosphatase (TNSALP)**. This deficiency leads to an accumulation of inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. **Why Vitamin D is Contraindicated:** In HPP, patients typically present with **hypercalcemia** and **hypercalciuria** because calcium cannot be deposited into the bone matrix due to the lack of alkaline phosphatase. Administering **Vitamin D** (Option A) increases intestinal calcium absorption and bone resorption, which severely exacerbates hypercalcemia and hypercalciuria. This can lead to nephrocalcinosis, renal failure, and vitamin D toxicity. Therefore, Vitamin D and calcium supplements are strictly contraindicated unless a co-existing deficiency is proven. **Analysis of Other Options:** * **Calcium chelating agents (Option B):** These are not standard treatments but are not contraindicated; in cases of severe hypercalcemic crisis, they may be used to lower serum calcium. * **Enzyme Replacement (Option C):** **Asfotase alfa** is the definitive, FDA-approved treatment for HPP. It is a recombinant TNSALP that improves mineralization and survival. * **Renal Dialysis (Option D):** While not a primary treatment for HPP, it may be required if the patient develops end-stage renal disease due to chronic nephrocalcinosis. **NEET-PG High-Yield Pearls:** * **Biochemical Hallmark:** Low serum Alkaline Phosphatase (ALP) levels (age-adjusted) and elevated serum Pyridoxal-5'-Phosphate (Vitamin B6). * **Clinical Sign:** Premature loss of deciduous teeth (before age 5) is a classic pediatric presentation. * **Radiology:** "Copper beaten skull" (craniosynostosis) and metaphyseal lucencies (resembling rickets).

Q: Which of the following is the most likely inheritance pattern in the given pedigree?

X-linked dominant. ***X-linked dominant*** - **No father-to-son transmission** from affected males, as fathers pass their Y chromosome (not X) to sons. - **All daughters of affected fathers** are affected because they inherit the father's X chromosome carrying the dominant allele. *Autosomal dominant* - Would show **father-to-son transmission** since the gene is located on autosomes, not sex chromosomes. - **Vertical transmission** pattern would be present but without the sex-specific inheritance seen in X-linked patterns. *Mitochondrial* - Shows **maternal inheritance to ALL children** regardless of sex, as mitochondria are inherited from the mother. - **No paternal transmission** occurs, and all offspring of affected mothers would be affected. *Autosomal recessive* - Typically shows **horizontal transmission** with affected individuals in the same generation (siblings). - **Carrier parents** are unaffected, leading to skipped generations and approximately **25% affected offspring**.

Q: In Crigler-Najjar syndrome type II, what is the primary defect?

Conjugation of bilirubin. **Explanation:** Crigler-Najjar syndrome (Type I and II) is a genetic disorder characterized by non-hemolytic unconjugated hyperbilirubinemia. The primary defect lies in the **conjugation of bilirubin** due to a deficiency of the enzyme **UDP-glucuronosyltransferase (UGT1A1)**. In Type II (Arias Syndrome), there is a partial deficiency (enzyme activity is typically <10% of normal), whereas Type I involves a complete absence of the enzyme. **Analysis of Options:** * **Option B (Correct):** Bilirubin must be conjugated with glucuronic acid by UGT1A1 to become water-soluble. A defect in this enzyme prevents conjugation, leading to a buildup of indirect (unconjugated) bilirubin. * **Option A:** Defective uptake of bilirubin by hepatocytes is characteristic of **Gilbert Syndrome** (which also involves UGT deficiency but to a lesser extent) and potentially certain drug interferences, but it is not the primary pathology of Crigler-Najjar. * **Option C:** Defective excretion of conjugated bilirubin into the bile canaliculi is seen in **Dubin-Johnson** and **Rotor syndromes**, which present with conjugated hyperbilirubinemia. * **Option D:** Bile duct obstruction causes **obstructive (post-hepatic) jaundice**, characterized by elevated conjugated bilirubin and alkaline phosphatase, not a genetic conjugation defect. **High-Yield Clinical Pearls for NEET-PG:** * **Type I vs. Type II:** Type I is severe, presents in neonates, and does not respond to Phenobarbital. Type II is milder and **responds to Phenobarbital**, which induces the remaining UGT1A1 enzyme activity. * **Kernicterus:** Highly likely in Type I due to very high unconjugated bilirubin; rare in Type II. * **Inheritance:** Type I is Autosomal Recessive; Type II is usually Autosomal Dominant with variable penetrance.

Q: Which one of the following is not a feature of Phenylketonuria?

Reduced tendon reflexes. **Phenylketonuria (PKU)** is an autosomal recessive disorder caused by a deficiency of the enzyme **phenylalanine hydroxylase (PAH)**, leading to the accumulation of phenylalanine and its metabolites (phenylketones). ### Explanation of Options: * **B. Reduced tendon reflexes (Correct Answer):** This is NOT a feature of PKU. In fact, patients with untreated PKU typically exhibit **hyperreflexia** (increased tendon reflexes) and spasticity. This occurs due to the toxic effects of phenylalanine on the developing central nervous system, leading to upper motor neuron signs rather than lower motor neuron signs. * **A. Severe mental retardation:** If left untreated, PKU leads to profound intellectual disability. High levels of phenylalanine interfere with amino acid transport across the blood-brain barrier and inhibit myelin formation. * **C. Enamel hypoplasia:** This is a documented clinical finding in children with PKU. The metabolic derangement during tooth development leads to defects in enamel formation. * **D. Vomiting in early infancy:** This is a common early clinical presentation. Infants often present with persistent vomiting, which can sometimes be misdiagnosed as pyloric stenosis. ### High-Yield Clinical Pearls for NEET-PG: * **Mousy/Musty Odor:** Due to the presence of **phenylacetic acid** in sweat and urine. * **Hypopigmentation:** Phenylalanine is a competitive inhibitor of tyrosinase. Reduced melanin synthesis leads to fair skin, blonde hair, and blue eyes. * **Diagnosis:** Screened via the **Guthrie Test** (bacterial inhibition assay). * **Management:** Dietary restriction of phenylalanine and supplementation of **Tyrosine** (which becomes an essential amino acid in these patients). * **Maternal PKU:** If a pregnant woman has high phenylalanine levels, the fetus may suffer from microcephaly, congenital heart defects, and mental retardation, even if the fetus is only a carrier.

Q: All of the following are X-linked recessive disorders except?

Ataxia telangiectasia. **Explanation:** The correct answer is **Ataxia telangiectasia**, which is an **Autosomal Recessive (AR)** disorder. It is caused by a mutation in the *ATM* gene on chromosome 11, leading to defective DNA repair (specifically double-strand breaks). Clinically, it presents with the triad of cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency (IgA deficiency). **Analysis of Options:** * **Chronic Granulomatous Disease (CGD):** The most common form (approx. 70%) is **X-linked recessive**, caused by a mutation in the *CYBB* gene encoding the gp91phox subunit of NADPH oxidase. This leads to an inability of phagocytes to produce superoxide radicals, resulting in recurrent infections with catalase-positive organisms. * **Fragile X Syndrome:** This is an **X-linked dominant** disorder (with variable expressivity/reduced penetrance) often grouped under X-linked inheritance in competitive exams. It is caused by a CGG trinucleotide repeat expansion in the *FMR1* gene. * **Lesch-Nyhan Syndrome:** This is a classic **X-linked recessive** disorder caused by a deficiency of the enzyme **HGPRT** in the purine salvage pathway. It is characterized by hyperuricemia, gout, intellectual disability, and hallmark self-mutilating behavior. **High-Yield Clinical Pearls for NEET-PG:** * **Ataxia Telangiectasia:** Look for elevated **Alpha-fetoprotein (AFP)** levels in a child with gait instability; this is a highly specific diagnostic marker. * **X-linked Recessive Mnemonic:** "The **G**reedy **H**unter **L**oves **F**abry's **C**olorful **D**iamonds" (**G**6PD, **H**emophilia, **L**esch-Nyhan, **F**ragile X*, **C**GD, **D**uchenne MD). * **DNA Repair Defects:** Remember that Ataxia telangiectasia, Xeroderma pigmentosum, and Fanconi anemia are all **Autosomal Recessive**.

Q: Pyrimidine 5'-Nucleotidase deficiency presents clinically as:

Anemia. **Explanation:** **Pyrimidine 5'-Nucleotidase (P5N) deficiency** is an autosomal recessive condition that primarily results in **Hereditary Nonspherocytic Hemolytic Anemia**. **Why Anemia is the Correct Answer:** P5N is an enzyme responsible for the dephosphorylation of pyrimidine nucleotides (UMP and CMP) into nucleosides, allowing them to exit the mature erythrocyte. In its absence, pyrimidine nucleotides accumulate within the red blood cell. These excess nucleotides interfere with glycolysis and pentose phosphate pathway enzymes. Furthermore, the accumulated pyrimidines are mistakenly incorporated into RNA degradation processes, leading to the characteristic histological finding of **coarse basophilic stippling** on a peripheral blood smear. The metabolic stress and membrane damage eventually lead to premature destruction of RBCs (hemolysis). **Why Other Options are Incorrect:** * **Dementia & Seizures:** While some metabolic disorders (like Lead poisoning) present with neurological symptoms, isolated P5N deficiency is clinically restricted to hematologic manifestations. It does not typically involve the central nervous system. * **Bleeding:** Bleeding disorders are associated with platelet dysfunction or coagulation factor deficiencies. P5N deficiency affects the erythrocyte metabolic pathway, not the primary or secondary hemostasis. **High-Yield Clinical Pearls for NEET-PG:** * **Basophilic Stippling:** P5N deficiency is the most common genetic cause of prominent basophilic stippling. * **Lead Poisoning Link:** Lead inhibits the P5N enzyme. Therefore, lead poisoning "mimics" P5N deficiency, presenting with similar basophilic stippling and hemolytic anemia. * **Diagnosis:** Suspect this in a patient with chronic hemolysis, normal osmotic fragility, and marked basophilic stippling.

Q: The genetic defect in Dubin-Johnson Syndrome is a mutation in which of the following?

Gene for multiple drug resistance protein 2 (MRP2). **Explanation:** **Dubin-Johnson Syndrome (DJS)** is an autosomal recessive disorder characterized by chronic, non-hemolytic **conjugated hyperbilirubinemia**. 1. **Why Option A is correct:** The fundamental defect in DJS is a mutation in the **ABCC2 gene**, which encodes the **Multidrug Resistance-associated Protein 2 (MRP2)**. MRP2 is an ATP-dependent transporter located on the canalicular membrane of hepatocytes. It is responsible for the efflux of conjugated bilirubin and other organic anions into the bile. A defect in this transporter leads to the accumulation of conjugated bilirubin within hepatocytes, which then leaks back into the blood. 2. **Why other options are incorrect:** * **Option B:** Mutations in the **UDP-glucuronosyltransferase (UGT1A1)** gene lead to unconjugated hyperbilirubinemia, seen in **Crigler-Najjar Syndrome** and **Gilbert Syndrome**. * **Option C:** DJS is an autosomal recessive condition linked to **Chromosome 10q24**, not chromosome 23 (Sex chromosomes). * **Option D:** 'Flash mutations' is not a standard genetic term associated with biliary transport disorders. **High-Yield Clinical Pearls for NEET-PG:** * **Black Liver:** A pathognomonic feature of DJS is a grossly **black/dark brown liver** due to the accumulation of epinephrine metabolites (melanin-like pigment) in lysosomes. * **Urinary Coproporphyrins:** Total urinary coproporphyrin levels are normal, but **Coproporphyrin I** constitutes >80% of the total (in normal individuals, Coproporphyrin III predominates). * **Rotor Syndrome vs. DJS:** Rotor syndrome is also a conjugated hyperbilirubinemia but lacks the liver pigmentation and has different urinary porphyrin patterns. * **Oral Cholecystography:** The gallbladder is typically **not visualized** in DJS.

Q: What is the chance of having cystic fibrosis if only one parent is affected and the other parent is a carrier?

50%. Cystic Fibrosis (CF) is an **Autosomal Recessive (AR)** disorder caused by mutations in the *CFTR* gene on chromosome 7 [1]. To manifest the disease, an individual must inherit two defective alleles (homozygous). In this scenario: * **Affected Parent:** Genotype is **aa** (homozygous recessive). * **Carrier Parent:** Genotype is **Aa** (heterozygous). Using a Punnett Square (aa × Aa): * 50% of offspring will be **Aa** (Carriers) * 50% of offspring will be **aa** (Affected) Thus, there is a **50% chance** of the child having cystic fibrosis [1]. This specific inheritance pattern (Affected × Carrier) mimics a pseudo-dominant pattern. **Analysis of Incorrect Options:** * **A (25%):** This is the risk when **both parents are carriers** (Aa × Aa). * **C (75%):** This is the probability of an offspring being "unaffected" (either carrier or healthy) when both parents are carriers. * **D (100%):** This occurs only if **both parents are affected** (aa × aa). **NEET-PG High-Yield Pearls:** * **Most common mutation:** ΔF508 (Class II mutation – protein misfolding and degradation). * **Diagnosis:** Sweat Chloride Test (>60 mEq/L) is the gold standard. * **Clinical Triad:** Chronic sinopulmonary disease, exocrine pancreatic insufficiency, and meconium ileus (in neonates) [2]. * **Infertility:** 95% of males are infertile due to Congenital Bilateral Absence of Vas Deferens (CBAVD). * **Organism:** *Pseudomonas aeruginosa* is the most common cause of pulmonary infections in older CF patients.

Q: The ferric chloride (FeCl3) test for phenylketonuria in urine typically results in which color?

Green. ### Explanation **Correct Answer: A. Green** **Medical Concept:** Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of the enzyme **phenylalanine hydroxylase**. This leads to the accumulation of phenylalanine, which is alternatively metabolized into **phenylpyruvate** (a phenylketone). In the Ferric Chloride (FeCl₃) test, the ferric ions react with the enol group of phenylpyruvate in the urine to produce a characteristic **transient blue-green or olive-green color**. **Analysis of Incorrect Options:** * **B. Blue:** While some metabolites can produce a bluish tint, the classic diagnostic color for PKU is green. A deep blue color is more characteristic of Alkaptonuria (though it typically turns black upon standing). * **C. Red:** A red or reddish-brown color in a FeCl₃ test is indicative of **salicylates** (aspirin) or **ketone bodies** (acetoacetate) in the urine. * **D. Purple:** A purple color is typically seen in the presence of salicylates or phenol derivatives. **High-Yield Clinical Pearls for NEET-PG:** * **The "Mousy" Odor:** Phenylacetic acid in the sweat and urine of PKU patients gives off a characteristic "mousy" or "musty" odor. * **Screening vs. Diagnosis:** The FeCl₃ test is a non-specific screening tool and is no longer the gold standard. Modern screening uses **Guthrie’s bacterial inhibition assay** or Tandem Mass Spectrometry. * **Associated Findings:** Patients often present with intellectual disability, seizures, and **hypopigmentation** (fair skin/blue eyes) because phenylalanine is a competitive inhibitor of tyrosinase, impairing melanin synthesis. * **Other FeCl₃ Results:** * Alkaptonuria (Homogentisic acid) → Transient Blue/Green. * Maple Syrup Urine Disease (Ketoacids) → Navy Blue. * Tyrosinemia → Pale Green.

Question 1

All are true about Fabry disease, EXCEPT:

Accepted Answer

Retinitis pigmentosa is well described in Fabry disease

Answer

X-linked recessive disorder

Answer

Premature atherosclerosis is seen

Answer

Accumulation of ceramide trihexoside in nerves and blood vessels

Question 2

Which treatment is contraindicated in hypophosphatasia?

Accepted Answer

Vitamin D

Answer

Calcium chelating agent

Answer

Enzyme replacement

Answer

Renal dialysis

Question 3

Which of the following is the most likely inheritance pattern in the given pedigree?

Accepted Answer

X-linked dominant

Answer

Autosomal dominant

Answer

Mitochondrial

Answer

Autosomal recessive

Question 4

In Crigler-Najjar syndrome type II, what is the primary defect?

Accepted Answer

Conjugation of bilirubin

Answer

Uptake of bilirubin by liver cells

Answer

Excretion of bilirubin

Answer

Bile duct obstruction preventing bile passage into the intestine

Question 5

Which one of the following is not a feature of Phenylketonuria?

Accepted Answer

Reduced tendon reflexes

Answer

Severe mental retardation

Answer

Enamel hypoplasia

Answer

Vomiting in early infancy

Question 6

All of the following are X-linked recessive disorders except?

Accepted Answer

Ataxia telangiectasia

Answer

Chronic granulomatous disease

Answer

Fragile X syndrome

Answer

Lesch-Nyhan syndrome

Question 7

Pyrimidine 5'-Nucleotidase deficiency presents clinically as:

Accepted Answer

Anemia

Answer

Dementia

Answer

Seizures

Answer

Bleeding

Question 8

The genetic defect in Dubin-Johnson Syndrome is a mutation in which of the following?

Accepted Answer

Gene for multiple drug resistance protein 2 (MRP2)

Answer

UDP-glucuronosyltransferase gene

Answer

A mutation on chromosome 23

Answer

A gene associated with 'flash mutations'

Question 9

What is the chance of having cystic fibrosis if only one parent is affected and the other parent is a carrier?

Accepted Answer

50%

Answer

25%

Answer

75%

Answer

100%

Question 10

The ferric chloride (FeCl3) test for phenylketonuria in urine typically results in which color?

Accepted Answer

Green

Answer

Blue

Answer

Red

Answer

Purple

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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