Genetic Disorders and Biochemical Pathology — MCQs

A child presents with fatigue and hepatomegaly. Liver enzymes (ALT, AST) are elevated. Ketosis was significant. Liver biopsy shows excess glycogen accumulation. After feeding, blood glucose levels rise, but there is no rise in glucose after overnight fasting. Which of the following enzyme deficiencies is most likely responsible for this presentation?

Genetic Disorders and Biochemical Pathology Indian Medical PG Practice Questions and MCQs

Question 621: Which of the following accumulates in the mucopolysaccharidosis associated with Natowicz disease?

A. Dermatan sulfate
B. Hyaluronic acid (Correct Answer)
C. Heparan sulfate
D. Keratan sulfate

Explanation: ***Hyaluronic acid***- Natowicz disease is synonymous with **Mucopolysaccharidosis type IX (MPS IX)**, a highly rare lysosomal storage disorder.- This condition is caused by a deficiency in the enzyme **hyaluronidase (HYAL1)**, which results in the failure to degrade **hyaluronic acid**, leading to its massive accumulation.*Dermatan sulfate*- Accumulation of **dermatan sulfate** is the defining characteristic of MPS I (Hurler, Scheie), MPS II (Hunter), and MPS VI (Maroteaux-Lamy).- These disorders generally involve widespread visceral, skeletal, and neurological pathology, unlike the localized features of MPS IX.*Heparan sulfate*- **Heparan sulfate** accumulates primarily in the various subtypes of **Sanfilippo syndrome (MPS III)**, as well as MPS I and II.- MPS III is predominantly characterized by progressive **neurocognitive decline** with relatively mild somatic features compared to other MPS types.*Keratan sulfate*- Accumulation of **keratan sulfate** is the metabolic hallmark of **Morquio syndrome (MPS IV)**, a disorder primarily presenting with severe skeletal dysplasia.- MPS IV involves deficiencies in either *N*-acetylgalactosamine-6-sulfatase or $\beta$-galactosidase, not hyaluronidase.

Question 622: Which of the following is excreted in the urine of patients with pentosuria?

A. L-Xylulose (Correct Answer)
B. D-Lactose
C. D-Ribulose
D. D-Ribose

Explanation: ***L-Xylulose***- Pentosuria is a benign, autosomal recessive disorder caused by a deficiency in the enzyme **L-xylulose reductase** (or xylitol dehydrogenase), which is part of the **glucuronic acid pathway (GAA)**.- This deficiency prevents the conversion of **L-xylulose** (a pentose intermediate) to xylitol, leading to the accumulation and subsequent excretion of L-xylulose in the urine.*D-Ribose*- D-Ribose is an **aldopentose** sugar crucial for forming the backbone of **RNA**, **ATP**, and various coenzymes (e.g., NAD, FAD).- Its metabolism is primarily handled by the **pentose phosphate pathway**; its excretion is not the hallmark of the enzyme deficiency in pentosuria.*D-Ribulose*- D-Ribulose is a **ketopentose** that plays a key role as an intermediate in the **pentose phosphate pathway** (PPP), specifically forming xylulose 5-phosphate.- Although it is a pentose, its accumulation and excretion are not characteristic findings of the defective **L-xylulose reductase** enzyme in pentosuria.*D-Lactose*- D-Lactose is a **disaccharide** composed of glucose and galactose, derived from milk, and is not a pentose sugar.- Lactosuria (lactose excretion) is typically related to high dietary intake or severe disorders affecting **lactose metabolism** or hepatic function, which is unrelated to the biochemical defect causing pentosuria.

Question 623: A 3-month-old baby presents with severe hepatomegaly, cataracts in both eyes, lethargy, and hypotonia. Based on these symptoms, which enzyme deficiency is most likely involved?

A. Hepatic Glucose-6-Phosphatase
B. Galactose-1-Phosphate Uridyl Transferase (Correct Answer)
C. UDP-Galactose-4-Epimerase
D. Galactokinase

Explanation: ***Galactose-1-Phosphate Uridyl Transferase*** - **GALT** deficiency causes **Classic Galactosemia**, which is characterized by the accumulation of **galactose-1-phosphate**, leading to widespread organ damage. - The classic presentation in neonates includes **hepatomegaly**, **jaundice**, failure to thrive, hypoglycemia, **E. coli sepsis**, developmental delay, and pathognomonic **cataracts**. - This is the **most severe form** of galactosemia and matches all the clinical features in this case. *Galactokinase* - Deficiency of **Galactokinase (GALK)** leads to a milder form of galactosemia where **galactitol** accumulates, primarily causing **cataracts** in infancy. - Systemic symptoms like **hepatomegaly**, liver failure, and severe lethargy, as seen in this 3-month-old, are typically **absent** in GALK deficiency. *UDP-Galactose-4-Epimerase* - **GALE** deficiency is the rarest form of galactosemia with variable clinical severity. - While severe forms can present with symptoms similar to classic galactosemia, they are extremely rare and account for less than 5% of galactosemia cases. - The combination of severe hepatomegaly and cataracts at 3 months is most characteristic of **GALT deficiency**, not GALE deficiency. *Hepatic Glucose-6-Phosphatase* - Deficiency of this enzyme causes **Von Gierke disease** (GSD Type I), characterized by significant **hepatomegaly** and severe **fasting hypoglycemia**. - While it causes hepatomegaly and lethargy (from hypoglycemia), it is **not** associated with the development of **cataracts**, which differentiates it from galactosemia.

Question 624: Zellweger syndrome is associated with which cellular organelle?

A. C. Lysosomes
B. D. Ribosomes
C. B. Mitochondria
D. A. Peroxisomes (Correct Answer)

Explanation: ***A. Peroxisomes*** - Zellweger syndrome is a severe disorder belonging to the group of **peroxisomal biogenesis disorders (PBDs)**, resulting from a failure to form functional peroxisomes due to mutations in *PEX* genes. - Functional peroxisomes are essential for the metabolism of substances like **very long-chain fatty acids (VLCFAs)** and plasmalogens; their absence leads to the accumulation of these toxic molecules. *B. Mitochondria* - **Mitochondria** are the powerhouse organelles responsible for cellular energy production via oxidative phosphorylation. - Mitochondrial disorders present with distinct features like lactic acidosis, myopathy, and neurodegeneration, which differ from the characteristic peroxisomal dysfunction seen in Zellweger syndrome. *C. Lysosomes* - **Lysosomes** are crucial for degrading cellular waste products and macromolecules; defects in these organelles cause **lysosomal storage diseases** (e.g., mucopolysaccharidoses). - Although some symptoms overlap, Zellweger syndrome is specifically defined by **peroxisomal dysfunction**, not primary lysosomal enzyme deficiency. *D. Ribosomes* - **Ribosomes** are responsible for synthesizing proteins via translation of mRNA. - Defects in ribosomes typically impair **global protein synthesis** or specific tissue development (ribosomopathies), which is distinct from the primary metabolic defects seen in Zellweger syndrome.

Question 625: A family pedigree chart is given below. Identify the mode of inheritance of this condition. ![img-29.jpeg](img-29.jpeg)

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

Explanation: ***Autosomal dominant*** - The trait is seen in **every generation** (vertical transmission), and affected parents (individuals 1 and 2) have an unaffected child (individual 7), which is a hallmark of dominant inheritance. - There is **male-to-male transmission** from the affected father (individual 4) to his son (individual 9), which rules out X-linked inheritance. *Autosomal recessive* - This is incorrect because two affected parents (1 and 2) have an unaffected offspring (7). In autosomal recessive inheritance, two affected parents (genotype **aa**) can only produce affected offspring. - The trait does not **skip generations**, which is a typical feature of recessive inheritance patterns. *X-linked recessive* - This is ruled out because an affected mother (2) has an unaffected son (7). In X-linked recessive traits, an affected mother (genotype **X<sup>a</sup>X<sup>a</sup>**) must pass the affected allele to all her sons, meaning all her sons would be affected. - Also, an unaffected couple (7 and 8) would need to have an affected child for this pattern to be considered, which is not the case here. *X-linked dominant* - The presence of **male-to-male transmission** (from father 4 to son 9) makes this mode of inheritance impossible. - In X-linked inheritance, a father passes his **Y chromosome** to his sons and his X chromosome to his daughters, so an affected father cannot have an affected son via this mechanism.

Question 626: A deficiency of Glucose-6-Phosphatase is associated with which of the following bilirubin patterns?

A. Direct bilirubin normal, indirect bilirubin increased, and urobilinogen normal (Correct Answer)
B. Indirect bilirubin increased, direct bilirubin normal, and raised urine urobilinogen
C. Direct bilirubin increased, indirect bilirubin decreased, and urine urobilinogen/urobilin increased
D. Raised direct bilirubin, normal indirect bilirubin, and absent urine bilirubin

Explanation: ***Direct bilirubin normal, indirect bilirubin increased, and urobilinogen normal*** - Glucose-6-Phosphatase (G6Pase) deficiency causes **Glycogen Storage Disease Type I (von Gierke disease)**, which is primarily characterized by severe **hypoglycemia**, hepatomegaly, lactic acidosis, and hyperuricemia. - While jaundice is NOT a classical feature of von Gierke disease, some patients may show mild elevation of **unconjugated (indirect) bilirubin**. - The proposed mechanism involves accumulation of **glucuronic acid** (a metabolic byproduct that cannot be converted to glucose due to G6Pase deficiency), which may competitively inhibit **UDP-glucuronyltransferase (UGT1A1)**, the enzyme responsible for bilirubin conjugation. - This results in increased **indirect (unconjugated) bilirubin** with normal direct bilirubin and normal urobilinogen, similar to the pattern seen in Gilbert syndrome. *Indirect bilirubin increased, direct bilirubin normal, and raised urine urobilinogen* - This pattern with raised urobilinogen is more characteristic of **hemolytic conditions** where excessive red blood cell breakdown overwhelms the liver's conjugation capacity. - The increased urobilinogen suggests increased enterohepatic circulation of bilirubin metabolites, which is not a typical feature of G6Pase deficiency. - While indirect bilirubin may be elevated in von Gierke disease, the raised urobilinogen makes this pattern less specific. *Direct bilirubin increased, indirect bilirubin decreased, and urine urobilinogen/urobilin increased* - This pattern is **internally contradictory** and does not match any known pathophysiological mechanism in G6Pase deficiency. - If G6Pase deficiency affects bilirubin metabolism, it would impair conjugation (leading to **increased** indirect bilirubin), not decrease it. - Additionally, decreased indirect bilirubin with increased direct bilirubin would require enhanced conjugation, which is opposite to the proposed mechanism of UGT1A1 inhibition. *Raised direct bilirubin, normal indirect bilirubin, and absent urine bilirubin* - This pattern represents **conjugated hyperbilirubinemia** with defective biliary excretion, characteristic of **Dubin-Johnson syndrome** or **Rotor syndrome**. - These conditions involve defects in hepatocyte transport proteins (MRP2 in Dubin-Johnson), not impaired conjugation. - This pattern is inconsistent with the proposed mechanism in G6Pase deficiency, where impaired conjugation would increase **unconjugated** bilirubin.

Question 627: A child presents with developmental delay and coarse facial features. Enzyme assay reveals a deficiency of α-L-iduronidase. Which of the following substances is most likely to accumulate in this condition?

A. Only Dermatan sulfate
B. Heparan sulfate + Chondroitin sulfate
C. Dermatan sulfate + Chondroitin sulfate
D. Dermatan sulfate + Heparan sulfate (Correct Answer)

Explanation: ***Dermatan sulfate + Heparan sulfate*** - The presenting features of developmental delay and **coarse facial features** point towards a Mucopolysaccharidosis (MPS). - A deficiency of **α-L-iduronidase** is diagnostic of **MPS Type I (Hurler syndrome)**, which leads to the accumulation of **Dermatan sulfate** and **Heparan sulfate**. *Dermatan sulfate + Chondroitin sulfate* - While **Dermatan sulfate** accumulates in MPS I, **Chondroitin sulfate** accumulation is characteristic of **MPS IV (Morquio syndrome)**, which has different clinical features (skeletal dysplasia, normal intelligence). - This combination does not correctly represent the primary storage products of **MPS I**. *Only Dermatan sulfate* - Both **MPS I (Hurler syndrome)** and **MPS II (Hunter syndrome)** result in accumulation of **both Dermatan sulfate AND Heparan sulfate**, not dermatan sulfate alone. - Listing dermatan sulfate alone is incomplete and does not accurately reflect the biochemical defect in **α-L-iduronidase deficiency**. *Heparan sulfate + Chondroitin sulfate* - **Heparan sulfate** does accumulate in MPS I, but the co-accumulation is with **Dermatan sulfate**, not Chondroitin sulfate. - **Chondroitin sulfate** accumulation is characteristic of **MPS IV (Morquio syndrome)**, which involves different enzyme deficiencies.

Question 628: Which of the following is a mitochondrial inheritance disorder?

A. Achondroplasia
B. Cystic fibrosis
C. Williams syndrome
D. Kearns-Sayre syndrome (Correct Answer)

Explanation: ***Kearns-Sayre syndrome*** - It is a classic example of a **mitochondrial encephalomyopathy** resulting from large-scale deletions or duplications of mitochondrial DNA (**mtDNA**). - It is characterized clinically by the triad of **chronic progressive external ophthalmoplegia (CPEO)**, **retinitis pigmentosa**, and onset before age 20. - Follows **maternal inheritance** pattern typical of mitochondrial disorders. *Williams syndrome* - Williams syndrome is a disorder caused by a **microdeletion** of several genes on chromosome 7 (7q11.23). - It is inherited in an **autosomal dominant** fashion, though most cases arise spontaneously. *Achondroplasia* - This is the most common form of genetic dwarfism caused by a mutation in the **FGFR3 gene** (Fibroblast Growth Factor Receptor 3). - It exhibits an **autosomal dominant** inheritance pattern. *Cystic fibrosis* - Cystic fibrosis is caused by mutations in the **CFTR gene** (Cystic Fibrosis Transmembrane conductance Regulator) on chromosome 7. - It is transmitted via an **autosomal recessive** inheritance pattern.

Question 629: A neonate presents with seizures and is found to have a cherry red spot on fundus examination. Enzyme assay reveals deficiency of hexosaminidase A. Which of the following substances is most likely to be accumulated in this patient?

A. GM1 ganglioside
B. Sphingomyelin
C. GM2 ganglioside (Correct Answer)
D. Glucocerebroside

Explanation: ***GM2 ganglioside*** - Deficiency of **Hexosaminidase A** results in the accumulation of **GM2 ganglioside**, defining features of **Tay-Sachs disease**. - The accumulation of GM2 ganglioside in the retina's ganglion cells causes the characteristic **cherry red spot** on fundus examination. *GM1 ganglioside* - The accumulation of **GM1 ganglioside** occurs in **GM1 gangliosidosis**, due to a deficiency of **β-galactosidase**. - GM1 gangliosidosis typically presents with coarse facial features, hepatosplenomegaly, and skeletal deformities (**dysostosis multiplex**), features not always prominent in Tay-Sachs. *Sphingomyelin* - Accumulation of **Sphingomyelin** is the diagnostic feature of **Niemann-Pick disease** (especially Type A), caused by a deficiency of **sphingomyelinase**. - While Niemann-Pick Type A also causes a cherry red spot, it is classically associated with rapid neurodegeneration and marked **hepatosplenomegaly** and **foam cells** (lipid-laden macrophages). *Glucocerebroside* - This lipid accumulates in **Gaucher disease** because of deficient **glucocerebrosidase** activity. - Gaucher disease is characterized by bony involvement, pancytopenia, and massive **hepatosplenomegaly**, and does not typically feature the cherry red spot.

Question 630: A child presents with fatigue and hepatomegaly. Liver enzymes (ALT, AST) are elevated. Ketosis was significant. Liver biopsy shows excess glycogen accumulation. After feeding, blood glucose levels rise, but there is no rise in glucose after overnight fasting. Which of the following enzyme deficiencies is most likely responsible for this presentation?

A. Glucose-6-phosphatase (Correct Answer)
B. Liver phosphorylase
C. Muscle phosphorylase
D. Phosphofructokinase

Explanation: ***Glucose-6-phosphatase*** - This deficiency is characteristic of Glycogen Storage Disease type I (**GSD I** or **Von Gierke disease**), which prevents the final step of both glycogenolysis and gluconeogenesis (conversion of **Glucose-6-Phosphate** to free glucose). - The inability to release free glucose from the liver, especially during fasting, causes severe **fasting hypoglycemia**, significant **ketosis**, and massive **hepatomegaly** due to trapped glycogen and fat accumulation. *Liver phosphorylase* - Deficiency in **Liver phosphorylase** (GSD VI or Hers disease) impairs the breakdown of glycogen but does not affect the gluconeogenesis pathway. - While it leads to hepatomegaly and hypoglycemia, the symptoms are generally **milder** than GSD I, and the profound metabolic derangements (severe ketosis, lactic acidosis) seen in this case are typically less pronounced. *Muscle phosphorylase* - This enzyme deficiency, known as **GSD V** or **McArdle disease**, primarily affects the skeletal muscle, leading to muscle pain, cramps, and **exercise intolerance**. - It does not cause hepatomegaly or issues with hepatic glucose release and therefore is an **unlikely** cause of fasting hypoglycemia in a child. *Phosphofructokinase* - Phosphofructokinase (GSD VII or **Tarui disease**) deficiency affects both muscle and erythrocytes, presenting similar to McArdle disease with **exercise intolerance** and often mild hemolysis. - PFK deficiency primarily affects glycolysis and does not directly impair the liver's ability to release glucose via **gluconeogenesis** or the final G6Pase step during fasting.

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