Genetic Disorders and Biochemical Pathology Practice Questions

Q: Megaloblastic anemia resistant to treatment is seen with which of the following conditions?

Orotic aciduria. **Explanation:** **Orotic Aciduria** is the correct answer because it causes a unique form of megaloblastic anemia that is **refractory (resistant)** to treatment with Vitamin B12 and Folic acid. 1. **Mechanism (Why C is correct):** Hereditary Orotic Aciduria (Type I) is caused by a deficiency of the bifunctional enzyme **UMP Synthase** (Orotate phosphoribosyltransferase and OMP decarboxylase). This block prevents the conversion of orotic acid to UMP, leading to a **pyrimidine deficiency**. Since pyrimidines are essential for DNA synthesis, their absence results in megaloblastic changes in the bone marrow. Because the defect is downstream of the folate/B12 pathways, supplementing these vitamins does not bypass the block. Treatment requires **Uridine supplementation**, which provides a source of pyrimidines via the salvage pathway. 2. **Why A and B are incorrect:** * **Anticonvulsant therapy:** Drugs like Phenytoin interfere with folate absorption or metabolism. This anemia **responds** to folic acid supplementation. * **Hepatic cirrhosis:** Megaloblastic changes here are usually due to poor dietary intake of folate, increased requirements, or direct ethanol toxicity. These typically **respond** to nutritional correction. **High-Yield Clinical Pearls for NEET-PG:** * **Differentiating Feature:** Unlike Ornithine Transcarbamylase (OTC) deficiency (where orotic acid is also high), Hereditary Orotic Aciduria presents with **normal ammonia levels** and **megaloblastic anemia**. * **Clinical Presentation:** Look for a child with failure to thrive, developmental delay, and orotic acid crystals in the urine ("needle-shaped" crystals). * **Treatment of Choice:** Oral **Uridine triacetate** (bypasses the metabolic block).

Q: Which of the following is NOT an example of X-linked dominant inheritance?

Colour blindness. The correct answer is **A. Colour blindness**. **1. Why Colour Blindness is the correct answer:** Red-green colour blindness is a classic example of **X-linked recessive (XLR)** inheritance, not X-linked dominant. In XLR disorders, the condition typically affects males (who have only one X chromosome), while females are usually asymptomatic carriers. For a female to be affected, she must inherit two defective X chromosomes. **2. Analysis of Incorrect Options (X-linked Dominant Examples):** * **Hypophosphatemic Vitamin D-resistant rickets:** This is the most frequently cited example of **X-linked dominant (XLD)** inheritance. It involves a mutation in the *PHEX* gene, leading to renal phosphate wasting. Unlike nutritional rickets, it does not respond to standard Vitamin D doses. * **Incontinentia pigmenti:** This is an XLD disorder that is typically **lethal in males** in utero. It presents in females with characteristic skin lesions following the Lines of Blaschko (vesicular, verrucous, and hyperpigmented stages). * **Orofaciodigital syndrome (Type 1):** This is also an XLD condition characterized by malformations of the face, oral cavity, and digits. Similar to Incontinentia pigmenti, it is generally lethal in hemizygous males. **3. High-Yield NEET-PG Pearls:** * **X-linked Dominant (XLD) Rule:** An affected father will pass the trait to **all of his daughters** but **none of his sons** (since sons inherit his Y chromosome). * **Common XLD Disorders:** Alport Syndrome (some forms), Rett Syndrome, and Fragile X Syndrome (though it shows complex kinetics). * **Lethality:** Many XLD disorders (like Incontinentia pigmenti) show a skewed sex ratio in pedigrees because affected male fetuses result in spontaneous abortions.

Q: Which of the following enzymes is coded by the X-chromosome?

Iduronate sulfatase. **Explanation:** The question tests your knowledge of the inheritance patterns of **Mucopolysaccharidoses (MPS)**. Most lysosomal storage diseases are inherited in an autosomal recessive (AR) fashion; however, **Hunter Syndrome (MPS II)** is a notable exception as it is **X-linked recessive**. 1. **Correct Answer: Iduronate sulfatase (Option B)** This enzyme is deficient in **Hunter Syndrome (MPS II)**. Since the gene for Iduronate sulfatase is located on the X-chromosome (Xq28), the disease primarily affects males. This is a high-yield distinction in biochemistry. 2. **Incorrect Options:** * **alpha-L-Iduronidase (Option A):** Deficiency causes **Hurler Syndrome (MPS IH)**. Unlike Hunter syndrome, Hurler syndrome is **Autosomal Recessive**. It is generally more severe and presents with corneal clouding. * **beta-Galactosidase (Option C):** Deficiency leads to **Morquio Syndrome Type B (MPS IVB)** or GM1 gangliosidosis. It is inherited as an **Autosomal Recessive** trait. * **Hyaluronidase (Option D):** Deficiency leads to **MPS IX** (Natowicz syndrome), which is extremely rare and follows an **Autosomal Recessive** inheritance. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic for Hunter Syndrome:** "The **Hunter** aims for the **X** (X-linked) and needs **clear vision** (No corneal clouding)." * **Key Clinical Difference:** Hunter syndrome (MPS II) presents with aggressive behavior and skin nodules (pebbly skin), but **lacks the corneal clouding** seen in Hurler syndrome (MPS IH). * **Other X-linked Recessive Metabolic Disorders:** Fabry disease, Lesch-Nyhan syndrome, G6PD deficiency, and Chronic Granulomatous Disease (CGD).

Q: Which of the following conditions is inherited in an X-linked recessive pattern?

G-6-PD deficiency. **Explanation:** **G-6-PD Deficiency (Correct Answer):** Glucose-6-Phosphate Dehydrogenase (G-6-PD) deficiency is a classic **X-linked recessive (XLR)** disorder. The gene for the G6PD enzyme is located on the long arm of the X chromosome (Xq28). Because of this inheritance pattern, the condition primarily affects males, while females are typically asymptomatic carriers (unless skewed lyonization occurs). The deficiency leads to impaired production of NADPH, leaving red blood cells vulnerable to oxidative stress, resulting in episodic hemolytic anemia. **Analysis of Incorrect Options:** * **Neurofibromatosis (Type 1 and 2):** These are **Autosomal Dominant (AD)** conditions. NF1 is associated with the *NF1* gene on chromosome 17, and NF2 with the *merlin* gene on chromosome 22. * **Thalassemia:** Both Alpha and Beta thalassemias are **Autosomal Recessive (AR)** disorders involving mutations or deletions in the globin gene clusters (Chromosomes 16 and 11, respectively). * **Alkaptonuria:** This "inborn error of metabolism" (deficiency of homogentisate oxidase) follows an **Autosomal Recessive (AR)** inheritance pattern. **High-Yield Clinical Pearls for NEET-PG:** * **Common XLR Disorders Mnemonic:** "**G**o **L**ook **F**or **H**is **D**irty **C**at" (**G**6PD, **L**esch-Nyhan, **F**abry’s, **H**emophilia A/B, **D**uchenne Muscular Dystrophy, **C**olor Blindness). * **G-6-PD Triggers:** Hemolysis is often precipitated by fava beans, infections, or drugs (Primaquine, Sulphonamides, Nitrofurantoin). * **Morphology:** Look for **Heinz bodies** (denatured hemoglobin) and **Bite cells** (degluticytes) on a peripheral smear.

Q: Menke's disease is a disorder of which of the following transport mechanisms?

Impaired copper transport. **Explanation:** **Menkes Disease (Kinky Hair Syndrome)** is an X-linked recessive disorder caused by a mutation in the **ATP7A gene**. This gene encodes a P-type ATPase responsible for the efflux of copper from enterocytes into the portal circulation. In Menkes disease, copper is absorbed by intestinal cells but cannot be transported further, leading to **systemic copper deficiency**. 1. **Why Copper Transport is Correct:** Copper is a vital cofactor for several enzymes. Its deficiency leads to: * **Lysyl oxidase failure:** Results in defective collagen cross-linking (causing arterial tortuosity and bone abnormalities). * **Tyrosinase failure:** Leads to hypopigmentation. * **Cytochrome c oxidase failure:** Causes neurodegeneration and hypotonia. * **Dopamine β-hydroxylase failure:** Leads to catecholamine derangements. 2. **Why Other Options are Incorrect:** * **Zinc Transport:** Impaired zinc absorption (due to SLC39A4 mutation) causes **Acrodermatitis Enteropathica**, characterized by periorificial dermatitis, alopecia, and diarrhea. * **Magnesium Transport:** Disorders like Gitelman syndrome or Familial Hypomagnesemia with Hypercalciuria involve magnesium, but do not present with the "kinky hair" phenotype. * **Molybdenum Transport:** Molybdenum cofactor deficiency is a rare metabolic disorder presenting with early-onset seizures and lens ectopia, unrelated to copper metabolism. **High-Yield Clinical Pearls for NEET-PG:** * **Classic Triad:** Steely/Kinky hair (Pili torti), growth retardation, and progressive neurological deterioration. * **Diagnosis:** Low serum copper and low serum ceruloplasmin levels. * **Contrast with Wilson’s Disease:** Wilson’s is a defect in **ATP7B**, leading to copper *overload* (toxic accumulation in liver/brain), whereas Menkes is a defect in **ATP7A**, leading to systemic *deficiency*.

Q: Mucopolysaccharidoses are caused by?

Defects in the degradation of proteoglycans. **Explanation:** **1. Why the Correct Answer is Right:** Mucopolysaccharidoses (MPS) are a group of hereditary metabolic disorders characterized by the accumulation of **Glycosaminoglycans (GAGs)**, formerly known as mucopolysaccharides. These GAGs are the carbohydrate component of **proteoglycans**. Under normal physiological conditions, GAGs are degraded within **lysosomes** by a series of specific enzymes. MPS occurs due to a deficiency or defect in these lysosomal hydrolases, leading to the incomplete degradation and subsequent accumulation of GAGs in various tissues. Therefore, the core pathology is a **defect in the degradation** of proteoglycans. **2. Why the Incorrect Options are Wrong:** * **Option A:** The rate of synthesis of proteoglycans is normal in MPS; the problem lies entirely in their clearance. * **Option C:** The structure of the polysaccharides synthesized is initially normal. The "altered" structures found in tissues are actually partially degraded intermediates that cannot be broken down further. * **Option D:** While enzymes are insufficient, they are **glycosidases/sulfatases** (which break down carbohydrates), not **proteolytic enzymes** (which break down proteins). **3. High-Yield Clinical Pearls for NEET-PG:** * **Inheritance:** All MPS are **Autosomal Recessive**, EXCEPT **Hunter Syndrome (MPS II)**, which is **X-linked Recessive**. * **Corneal Clouding:** Present in most MPS (e.g., Hurler Syndrome) but notably **ABSENT in Hunter Syndrome**. * **Key Enzyme Deficiencies:** * **Hurler (MPS IH):** $\alpha$-L-iduronidase. * **Hunter (MPS II):** Iduronate sulfatase. * **Sanfilippo (MPS III):** Most common MPS; involves degradation of Heparan sulfate. * **Diagnosis:** Initial screening via urinary GAG levels; definitive diagnosis via enzyme assay or genetic testing.

Q: A 22-year-old woman with bipolar disorder develops neurologic manifestations over one year, including resting and intention tremors, rigidity, chorea, dysphagia, and dysarthria. Physical examination reveals bilateral Babinski signs. She has ring-like deposits of green material in the corneas bilaterally, without decreased vision. One year later, she experiences a 3-week illness with nausea, vomiting, malaise, and scleral icterus. Laboratory findings include serum AST 100 U/L, ALT 122 U/L, alkaline phosphatase 105 U/L, total bilirubin 4.5 mg/dL, glucose 77 mg/dL, and creatinine 0.9 mg/dL. Serologic tests for hepatitis A, B, and C are negative. This episode resolves without treatment, but she eventually develops cirrhosis. A mutation in a gene encoding for what substance is most likely present in this woman?

Copper-transporting ATPase. ### Explanation The clinical presentation of a young patient with **neuropsychiatric symptoms** (bipolar disorder, tremors, chorea, dysarthria), **Kayser-Fleischer (KF) rings** (green corneal deposits), and **recurrent liver injury** leading to cirrhosis is pathognomonic for **Wilson Disease** (Hepatolenticular Degeneration) [1]. **1. Why the Correct Answer is Right:** Wilson disease is an autosomal recessive disorder caused by a mutation in the **ATP7B gene** on chromosome 13. This gene encodes a **copper-transporting P-type ATPase** located in the hepatocytes. This protein is essential for: * Incorporating copper into **apoceruloplasmin** to form ceruloplasmin. * Excreting excess copper into the **bile** [2]. Deficiency leads to copper accumulation in the liver, brain (basal ganglia), and cornea, causing the multisystem manifestations described [1]. **2. Why the Other Options are Wrong:** * **A. α1-Antitrypsin:** Deficiency causes neonatal jaundice or adult-onset cirrhosis and emphysema. It does not cause KF rings or extrapyramidal neurological symptoms. * **B. CFTR:** Mutations cause Cystic Fibrosis. While it can cause biliary cirrhosis, the primary features are respiratory infections and pancreatic insufficiency. * **D. Galactose-1-phosphate uridyltransferase:** Deficiency causes classic Galactosemia, which presents in **neonates** with cataracts, hepatomegaly, and jaundice upon starting milk. **3. NEET-PG High-Yield Pearls:** * **Diagnosis:** Best initial test is **Serum Ceruloplasmin** (decreased); Gold standard is **Liver Biopsy** (increased copper content). * **KF Rings:** Located in the **Descemet’s membrane** of the cornea; seen via slit-lamp exam. * **Treatment:** Chelators like **D-Penicillamine** (first-line) or Trientine; Zinc (prevents absorption). * **Hemolysis:** Wilson disease can present with Coombs-negative hemolytic anemia [1].

Q: Hepatomegaly is a feature of all of the following, EXCEPT:

Hepatic porphyrias. ### Explanation The correct answer is **B. Hepatic porphyrias**. **1. Why Hepatic Porphyrias is the correct answer:** Hepatic porphyrias (such as Acute Intermittent Porphyria) are disorders of heme biosynthesis characterized by the accumulation of porphyrin precursors (ALA and PBG). While the liver is the primary site of the metabolic defect, these conditions typically present with **neurovisceral symptoms** (abdominal pain, neuropsychiatric issues) rather than structural changes like organomegaly. Unlike storage disorders, there is no massive accumulation of bulky macromolecules within the hepatocytes to cause significant hepatomegaly. **2. Why the other options are incorrect:** * **Hurler’s Disease (MPS I):** This is a lysosomal storage disorder where **Dermatan and Heparan sulfate** accumulate in the reticuloendothelial system, leading to significant hepatosplenomegaly and coarse facial features. * **Von Gierke’s Disease (GSD Type I):** Caused by a deficiency of **Glucose-6-Phosphatase**. Glycogen cannot be broken down into glucose and instead accumulates excessively in the liver and kidneys, leading to massive hepatomegaly and renomegaly. * **Niemann-Pick Disease:** A sphingolipidosis (deficiency of **Sphingomyelinase**) where sphingomyelin accumulates in macrophages. This results in prominent hepatosplenomegaly and a "cherry-red spot" on the macula. **Clinical Pearls for NEET-PG:** * **Massive Hepatomegaly:** Think Von Gierke’s (GSD I) or Gaucher’s Disease. * **Hepatomegaly + Hypoglycemia:** Think Glycogen Storage Diseases (Types I, III, VI). * **Hepatomegaly + Coarse Facies:** Think Mucopolysaccharidoses (Hurler/Hunter). * **Porphyria Tip:** The most common porphyria is *Porphyria Cutanea Tarda*, which may show mild liver damage/siderosis, but classic "Hepatic Porphyrias" are tested for their acute neurological presentations, not hepatomegaly.

Q: All of the following are features of Lesch-Nyhan syndrome EXCEPT:

Immunodeficiency. **Explanation:** **Lesch-Nyhan Syndrome (LNS)** is an X-linked recessive disorder caused by a complete deficiency of the enzyme **Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT)**. This enzyme is crucial for the purine salvage pathway, which recycles hypoxanthine and guanine into IMP and GMP. 1. **Why Immunodeficiency is the correct answer:** Immunodeficiency is **not** a feature of Lesch-Nyhan syndrome. While purine metabolism defects can cause immune issues (e.g., Adenosine Deaminase deficiency leads to SCID), HGPRT deficiency specifically affects the nervous system and uric acid metabolism without compromising the immune system. 2. **Analysis of incorrect options:** * **Hyperuricaemia (A):** Without HGPRT, purines cannot be salvaged and are instead degraded into uric acid. This leads to severe hyperuricemia, gouty arthritis, and nephrolithiasis (orange sand in diapers). * **Self-mutilation (B):** This is the hallmark behavioral feature of LNS. Patients exhibit compulsive biting of lips and fingers. * **Mental retardation (C):** The deficiency of HGPRT in the basal ganglia leads to neurological dysfunction, including intellectual disability, spasticity, and choreoathetosis. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic (HGPRT):** **H**yperuricemia, **G**out, **P**issed off (aggression/self-mutilation), **R**etardation (intellectual disability), **D**ys**T**onia. * **Inheritance:** X-linked recessive (affects males). * **Biochemical marker:** Increased levels of **PRPP** (Phosphoribosyl pyrophosphate) and increased de novo purine synthesis. * **Treatment:** Allopurinol or Febuxostat (manages uric acid but does not fix neurological symptoms).

Question 1

Megaloblastic anemia resistant to treatment is seen with which of the following conditions?

Accepted Answer

Orotic aciduria

Answer

Anticonvulsant therapy

Answer

Hepatic cirrhosis

Answer

All of the above

Question 2

One of the following disorders is due to maternal disomy of chromosome 15?

Accepted Answer

Angelman syndrome

Answer

Prader Willi syndrome

Answer

Hydatidiform mole

Answer

Klinefelter's syndrome

Question 3

Which of the following is NOT an example of X-linked dominant inheritance?

Accepted Answer

Colour blindness

Answer

Hypophosphatemic vitamin D-resistant rickets

Answer

Orofaciodigital syndrome

Answer

Incontinentia pigmenti

Question 4

Which of the following enzymes is coded by the X-chromosome?

Accepted Answer

Iduronate sulfatase

Answer

alpha-L-Iduronidase

Answer

beta-Galactosidase

Answer

Hyaluronidase

Question 5

Which of the following conditions is inherited in an X-linked recessive pattern?

Accepted Answer

G-6-PD deficiency

Answer

Neurofibromatosis

Answer

Thalassemia

Answer

Alkaptonuria

Question 6

Menke's disease is a disorder of which of the following transport mechanisms?

Accepted Answer

Impaired copper transport

Answer

Impaired zinc transport

Answer

Impaired magnesium transport

Answer

Impaired molybdenum transport

Question 7

Mucopolysaccharidoses are caused by?

Accepted Answer

Defects in the degradation of proteoglycans

Answer

An increased rate of synthesis of proteoglycans

Answer

The synthesis of polysaccharides with an altered structure

Answer

An insufficient amount of proteolytic enzymes

Question 8

A 22-year-old woman with bipolar disorder develops neurologic manifestations over one year, including resting and intention tremors, rigidity, chorea, dysphagia, and dysarthria. Physical examination reveals bilateral Babinski signs. She has ring-like deposits of green material in the corneas bilaterally, without decreased vision. One year later, she experiences a 3-week illness with nausea, vomiting, malaise, and scleral icterus. Laboratory findings include serum AST 100 U/L, ALT 122 U/L, alkaline phosphatase 105 U/L, total bilirubin 4.5 mg/dL, glucose 77 mg/dL, and creatinine 0.9 mg/dL. Serologic tests for hepatitis A, B, and C are negative. This episode resolves without treatment, but she eventually develops cirrhosis. A mutation in a gene encoding for what substance is most likely present in this woman?

Accepted Answer

Copper-transporting ATPase

Answer

a1-Antitrypsin

Answer

CFTR

Answer

Galactose-1-phosphate uridyltransferase

Question 9

Hepatomegaly is a feature of all of the following, EXCEPT:

Accepted Answer

Hepatic porphyrias

Answer

Hurler's Disease

Answer

Von Gierke's Disease

Answer

Nieman Pick Disease

Question 10

All of the following are features of Lesch-Nyhan syndrome EXCEPT:

Accepted Answer

Immunodeficiency

Answer

Hyperuricaemia

Answer

Self-mutilation

Answer

Mental retardation

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

On this page

Practice by Chapter

Want unlimited practice?