Genetic Disorders and Biochemical Pathology Practice Questions

Q: Cystic fibrosis is inherited as an autosomal recessive condition. A normal couple has one daughter affected with the disease. They are now planning to have another child. What is the chance of her sibling being affected by the disease?

1 in 4. ### Explanation **1. Why Option C (1 in 4) is Correct:** Cystic Fibrosis (CF) follows an **Autosomal Recessive (AR)** inheritance pattern. For a couple to have an affected child (genotype *aa*) despite being phenotypically normal, both parents must be **obligate carriers** (genotype *Aa*). According to Mendelian laws, when two carriers (*Aa x Aa*) conceive, the probability of offspring genotypes are: * 25% Homozygous Dominant (*AA*) – Normal * 50% Heterozygous (*Aa*) – Carrier (Normal phenotype) * **25% Homozygous Recessive (*aa*) – Affected** Since each pregnancy is an independent event, the probability of the next sibling being affected remains **1 in 4 (25%)**. **2. Why Other Options are Incorrect:** * **Option B (1 in 2):** This 50% risk occurs in Autosomal Dominant conditions if one parent is affected (*Aa x aa*) or in AR conditions if one parent is affected and the other is a carrier. * **Option D (3 in 4):** This 75% represents the probability of a child being **phenotypically normal** (sum of *AA* and *Aa*) in an AR cross. * **Note on Option A:** It is identical to Option C, which is the correct mathematical probability. **3. High-Yield Clinical Pearls for NEET-PG:** * **Molecular Defect:** Mutation in the **CFTR gene** (Cystic Fibrosis Transmembrane Conductance Regulator) located on **Chromosome 7**. * **Most Common Mutation:** **ΔF508** (deletion of phenylalanine at position 508), leading to protein misfolding and degradation in the Proteasome. * **Diagnosis:** Sweat Chloride Test (Gold Standard) showing chloride levels **>60 mEq/L**. * **Key Presentation:** Recurrent pulmonary infections (*Pseudomonas*), pancreatic insufficiency (steatorrhea), and **Infertility in males** (Congenital Bilateral Absence of Vas Deferens - CBAVD).

Q: Kinky hair disease is due to a defect in which of the following transport mechanisms?

Copper transport. **Explanation:** **Kinky Hair Disease (Menkes Disease)** is an X-linked recessive disorder caused by a mutation in the **ATP7A gene**. This gene encodes a P-type ATPase responsible for the absorption of dietary copper from the intestinal epithelium into the bloodstream and its transport across the blood-brain barrier. In Menkes disease, copper becomes trapped within intestinal mucosal cells, leading to a severe systemic **copper deficiency**. This deficiency impairs the function of copper-dependent enzymes (cuproenzymes), most notably **Lysyl Oxidase**. This enzyme is essential for cross-linking collagen and elastin; its failure results in the characteristic "kinky," brittle, and depigmented hair (pili torti), along with connective tissue defects and neurodegeneration. **Analysis of Incorrect Options:** * **A. Iron transport:** Defects in iron transport or metabolism typically lead to Hemochromatosis (overload) or Sideroblastic anemia, not kinky hair. * **B. Calcium transport:** Abnormalities in calcium transport are associated with disorders like hypoparathyroidism or rickets, affecting bone density and neuromuscular excitability. * **D. Magnesium transport:** Defects here lead to familial hypomagnesemia, which presents with seizures and tetany, but does not affect hair structure. **High-Yield Clinical Pearls for NEET-PG:** * **Menkes vs. Wilson:** Menkes is a defect in **ATP7A** (Copper deficiency/absorption failure). Wilson Disease is a defect in **ATP7B** (Copper overload/biliary excretion failure). * **Key Enzyme:** The "kinky hair" phenotype is specifically due to **Lysyl Oxidase** failure. * **Diagnosis:** Characterized by low serum copper and low serum ceruloplasmin levels. * **Mnemonic:** "Menkes is **A**bsorption (**ATP7A**); Wilson is **B**iliary (**ATP7B**)."

Q: Prader Willi syndrome is an example of?

Genomic imprinting. **Explanation:** **Prader-Willi Syndrome (PWS)** is a classic example of **Genomic Imprinting**, a phenomenon where the expression of a gene depends on whether it is inherited from the mother or the father. In PWS, there is a loss of function of specific genes on the **paternal chromosome 15 (15q11-q13)**. Under normal conditions, the maternal copy of these genes is silenced (imprinted) via methylation; therefore, if the paternal copy is deleted or inactive, the individual has no functional copies of these genes. **Analysis of Options:** * **Genomic Imprinting (Correct):** PWS occurs due to paternal deletion of 15q11-q13 (70%), Maternal Uniparental Disomy (25%), or imprinting center defects. Conversely, loss of the *maternal* copy of the same region leads to **Angelman Syndrome**. * **Digenic Inheritance:** Refers to diseases caused by the additive effect of mutations in two different genes (e.g., certain forms of Retinitis Pigmentosa). * **Translocation:** While a translocation can occasionally disrupt the PWS region, it is a structural mechanism, not the underlying genetic principle of the disease itself. * **Trisomy:** Refers to three copies of a chromosome (e.g., Trisomy 21 in Down Syndrome). PWS is typically associated with a microdeletion or disomy, not a trisomy. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Features:** Infantile hypotonia, hyperphagia leading to early-onset obesity, hypogonadism, small hands/feet, and mild intellectual disability. * **Diagnostic Gold Standard:** DNA Methylation analysis (detects abnormal imprinting). * **Mnemonic:** **P**rader-Willi = **P**aternal deletion; **A**ngelman = **M**aternal deletion (**A**bsent **M**other).

Q: The protein defective in cystinosis is responsible for which of the following functions?

Efflux of cysteine from the lysosome. ### Explanation **Correct Answer: D. Efflux of cysteine from the lysosome** **Mechanism:** Cystinosis is an autosomal recessive lysosomal storage disorder caused by a mutation in the **CTNS gene**, which encodes the protein **cystinosin**. Cystinosin is an integral membrane protein that functions as a specialized transporter responsible for the **efflux of cystine** (the disulfide dimer of cysteine) out of the lysosome into the cytosol. When this protein is defective, cystine accumulates and forms crystals within the lysosomes of various tissues, leading to cellular damage and organ dysfunction. **Analysis of Incorrect Options:** * **Options A & B:** These refer to **Cystinuria**, not cystinosis. Cystinuria is caused by a defect in the **COAL transporter** (Cysteine, Ornithine, Arginine, Lysine) in the proximal renal tubules and small intestine. It leads to kidney stones, not systemic lysosomal storage. * **Option C:** The defect in cystinosis is specifically localized to the **lysosomal membrane**, not the endoplasmic reticulum. **High-Yield Clinical Pearls for NEET-PG:** * **Infantile Nephropathic Cystinosis:** The most common and severe form. * **Renal Manifestation:** It is a classic cause of **Fanconi Syndrome** (proximal tubular acidosis, glycosuria, phosphaturia, and aminoaciduria) in children. * **Ocular Finding:** Photophobia due to **corneal cystine crystals** (visible on slit-lamp exam). * **Diagnosis:** Measurement of **intracellular cystine levels in polymorphonuclear leukocytes**. * **Treatment:** **Cysteamine**, which converts cystine into cysteine and cysteine-cysteamine mixed disulfides that can exit the lysosome via alternative transporters.

Q: What is a characteristic feature of alkaline phosphatase deficiency?

Absence of cementum.. **Explanation:** Alkaline Phosphatase (ALP) is a crucial enzyme for mineralization. In the genetic disorder **Hypophosphatasia**, there is a deficiency of the tissue-nonspecific alkaline phosphatase (TNSALP) isoenzyme. **1. Why "Absence of cementum" is correct:** ALP is essential for the formation of hydroxyapatite crystals. In the oral cavity, ALP activity is mandatory for the development of **acellular cementum** (the layer covering the tooth root). A deficiency leads to either complete absence or severe hypoplasia of cementum. Without cementum, the periodontal ligaments cannot attach the teeth to the alveolar bone, leading to the hallmark clinical sign: **premature spontaneous exfoliation of deciduous teeth** (especially incisors) without any signs of inflammation. **2. Why other options are incorrect:** * **Resorption of bone:** ALP deficiency causes a failure of mineralization (osteomalacia/rickets), not active resorption. Bone resorption is typically mediated by osteoclasts and acid phosphatase, which are not primarily affected here. * **Ankylosis of teeth:** Ankylosis is the pathological fusion of the tooth root to the bone. In ALP deficiency, the opposite occurs—teeth are loose and fall out because they fail to anchor to the bone due to the lack of cementum. **High-Yield Clinical Pearls for NEET-PG:** * **Biochemical Marker:** Low serum ALP levels and **elevated urinary phosphoethanolamine** are diagnostic. * **Radiology:** "Beaten copper" appearance of the skull and "bowing" of long bones. * **Key Symptom:** Premature loss of primary teeth (before age 4) is often the first presenting sign of the childhood form.

Q: Which enzyme is deficient in Marfan's syndrome?

None of the above. **Explanation:** **1. Why "None of the above" is correct:** Marfan’s syndrome is **not an enzymopathy**; it is a structural protein defect. It is an autosomal dominant disorder caused by a mutation in the **FBN1 gene** located on chromosome 15. This gene encodes **Fibrillin-1**, a large glycoprotein that serves as a scaffold for elastin. Defective fibrillin leads to mechanical weakness in connective tissues and excessive activation of TGF-β signaling, resulting in the characteristic skeletal, ocular, and cardiovascular manifestations. **2. Analysis of Incorrect Options:** * **A. Cystathionine beta-synthase:** Deficiency of this enzyme causes **Homocystinuria**. This is a crucial differential diagnosis for Marfan’s because both present with a "marfanoid habitus." However, Homocystinuria is autosomal recessive, involves intellectual disability, and features downward lens dislocation (ectopia lentis), whereas Marfan’s features upward dislocation. * **B. Lysyl oxidase:** This copper-dependent enzyme is responsible for cross-linking collagen and elastin. Its activity is impaired in **Menkes disease** (due to copper transport failure) and some forms of Ehlers-Danlos syndrome, but not in Marfan’s. * **C. Collagenase:** These are enzymes that break down native collagen. While matrix metalloproteinases (MMPs) play a role in tissue remodeling, their deficiency is not the primary cause of Marfan’s syndrome. **3. High-Yield Clinical Pearls for NEET-PG:** * **Chromosome:** 15 (Mnemonic: **15** letters in "Marfan Syndrome"). * **Cardiovascular:** Mitral Valve Prolapse (MVP) and **Aortic Root Dilation/Dissection** (most common cause of death). * **Ocular:** **Ectopia lentis** (typically **upward** and outward/Superotemporal). * **Skeletal:** Arachnodactyly, Pectus excavatum, and increased arm span to height ratio. * **Diagnosis:** Based on the **Ghent criteria**.

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 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.

Question 1

Cystic fibrosis is inherited as an autosomal recessive condition. A normal couple has one daughter affected with the disease. They are now planning to have another child. What is the chance of her sibling being affected by the disease?

Accepted Answer

1 in 4

Answer

1 in 2

Answer

3 in 4

Question 2

Kinky hair disease is due to a defect in which of the following transport mechanisms?

Accepted Answer

Copper transport

Answer

Iron transport

Answer

Calcium transport

Answer

Magnesium transport

Question 3

Prader Willi syndrome is an example of?

Accepted Answer

Genomic imprinting

Answer

Digenic inheritance

Answer

Translocation

Answer

Trisomy

Question 4

Which transporter is defective in renal glucosuria?

Accepted Answer

SGLT 2

Answer

GLUT 1

Answer

GLUT 2

Answer

SGLT 1

Question 5

The protein defective in cystinosis is responsible for which of the following functions?

Accepted Answer

Efflux of cysteine from the lysosome

Answer

Absorption of cysteine from the intestine

Answer

Absorption of cysteine from the renal tubules

Answer

Efflux of cysteine from the endoplasmic reticulum

Question 6

What is a characteristic feature of alkaline phosphatase deficiency?

Accepted Answer

Absence of cementum.

Answer

Resorption of bone.

Answer

Ankylosis of teeth.

Answer

All of the above.

Question 7

A 4-year-old girl presented with failure to thrive and megaloblastic anemia on peripheral blood smear. Despite Vitamin B12 and folate supplementation, her anemia did not improve. Enzyme assay from cultured PBMCs showed a deficiency of orotate phosphoribosyltransferase. What is the probable diagnosis?

Accepted Answer

Orotic aciduria

Answer

Orotate deficiency

Answer

Gout

Answer

Severe combined immunodeficiency (SCID)

Question 8

Which enzyme is deficient in Marfan's syndrome?

Accepted Answer

None of the above

Answer

Cystathionine beta-synthase

Answer

Lysyl oxidase

Answer

Collagenase

Question 9

Which of the following gene mutations occurs in cleidocranial dysplasia?

Accepted Answer

CBFA1 gene

Answer

CDFA1 gene

Answer

CBFA2 gene

Answer

None

Question 10

Which amino acids are excreted in the urine in cystinosis?

Accepted Answer

All of the above

Answer

Cystine

Answer

Ornithine

Answer

Arginine

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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