Genetic Disorders and Biochemical Pathology — MCQs

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

Question 691: Which enzyme deficiency leads to the accumulation of glucocerebroside in macrophages, resulting in Gaucher disease?

A. β-glucosidase (Correct Answer)
B. Hexosaminidase A
C. Sphingomyelinase
D. α-galactosidase A

Explanation: ***β-glucosidase*** - This enzyme, also known as **glucocerebrosidase**, is deficient in **Gaucher disease**. - Its deficiency leads to the harmful accumulation of **glucocerebroside** within lysosomes, particularly within **macrophages**. *Hexosaminidase A* - Deficiency of **Hexosaminidase A** is characteristic of **Tay-Sachs disease**, leading to the accumulation of **GM2 gangliosides**. - Tay-Sachs typically presents with neurological degeneration, rather than macrophage accumulation of glucocerebroside. *Sphingomyelinase* - A deficiency in **sphingomyelinase** is the cause of **Niemann-Pick disease**, resulting in the accumulation of **sphingomyelin**. - Niemann-Pick disease affects various organs and is characterized by hepatosplenomegaly and neurological deterioration in severe forms. *α-galactosidase A* - **Fabry disease** is caused by a deficiency in **α-galactosidase A**, leading to the buildup of **globotriaosylceramide (Gb3)**. - Fabry disease primarily affects the heart, kidneys, and nervous system, and does not involve glucocerebroside accumulation.

Question 692: A 45-year-old man presents with severe abdominal pain and neurological symptoms. His urine turns dark red upon standing. Which enzyme deficiency is most likely responsible for his condition?

A. ALA dehydratase
B. Porphobilinogen deaminase (Correct Answer)
C. Ferrochelatase
D. Coproporphyrinogen oxidase

Explanation: ***Porphobilinogen deaminase*** - Deficiency in **porphobilinogen deaminase (PBG deaminase)**, also known as **hydroxymethylbilane synthase**, is responsible for **acute intermittent porphyria (AIP)**. - This enzyme normally converts **porphobilinogen (PBG)** to **hydroxymethylbilane**; when deficient, there is **upstream accumulation** of **PBG** and **aminolevulinic acid (ALA)**. - These accumulated precursors are **neurotoxic**, causing the characteristic **severe abdominal pain** and **neurological symptoms** (peripheral neuropathy, psychiatric manifestations). - Urinary excretion of **PBG** causes urine to **darken to dark red/port-wine color upon standing** due to oxidation and polymerization. *ALA dehydratase* - Deficiency in **ALA dehydratase** causes **ALA dehydratase deficiency porphyria (ADP)**, also called **Doss porphyria**, which is extremely rare. - It presents similarly to AIP with neurovisceral symptoms, but the accumulation pattern differs (predominantly ALA rather than PBG). *Ferrochelatase* - Deficiency in **ferrochelatase** leads to **erythropoietic protoporphyria (EPP)**, characterized by accumulation of **protoporphyrin IX** in erythrocytes. - The main clinical manifestation is **photosensitivity** with severe pain, burning, and erythema upon sun exposure—not acute abdominal or neurological symptoms. *Coproporphyrinogen oxidase* - Deficiency in **coproporphyrinogen oxidase** causes **hereditary coproporphyria (HCP)**, which can present with neurovisceral attacks similar to AIP. - However, HCP also features **photosensitivity** (unlike AIP), and the classic presentation described with severe abdominal pain, neurological symptoms, and darkening urine most characteristically points to **AIP** caused by PBG deaminase deficiency.

Question 693: Which of the following statements is true regarding Fragile X syndrome?

A. Males typically have an IQ between 20-40
B. 10-20% of female carriers may have intellectual disabilities
C. Gain of function mutation in the FMR1 gene
D. Fragile X syndrome is caused by a trinucleotide CGG repeat expansion in the FMR1 gene. (Correct Answer)

Explanation: ***Fragile X syndrome is caused by a trinucleotide CGG repeat expansion in the FMR1 gene.*** - Fragile X syndrome is an **X-linked dominant genetic disorder** resulting from an expansion of a **CGG trinucleotide repeat** in the **FMR1 (Fragile X Mental Retardation 1) gene**. - This expansion leads to **hypermethylation** of the FMR1 gene promoter, causing **transcriptional silencing** and a deficiency of the fragile X mental retardation protein (FMRP). *10-20% of female carriers may have intellectual disabilities.* - While female carriers can be affected due to **skewed X-inactivation**, significant intellectual disability is **less common** and the percentage is typically lower than 10-20%. - Female carriers often present with milder symptoms, including a **higher risk of premature ovarian insufficiency (POI)** or mild cognitive deficits, but most have normal intelligence. *Males typically have an IQ between 20-40* - Males with Fragile X syndrome typically experience **moderate to severe intellectual disability**, with average IQs usually ranging between **35-55**, not 20-40 which would indicate a more profound disability. - The degree of intellectual impairment varies; while some males may have an IQ in this range, it is not the typical average for the majority. *Gain of function mutation in the FMR1 gene* - Fragile X syndrome is caused by a **loss-of-function mutation** in the FMR1 gene, specifically the absence or deficiency of its protein product, FMRP. - The **CGG repeat expansion** silences the FMR1 gene, leading to a lack of FMRP, which is essential for normal neural development and cognitive function.

Question 694: Lesch-Nyhan syndrome is caused by deficiency of which enzyme?

A. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (Correct Answer)
B. Xanthine oxidase
C. Adenine phosphoribosyltransferase (APRT)
D. Adenosine deaminase (ADA)

Explanation: ***Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)*** - **Lesch-Nyhan syndrome** is an **X-linked recessive disorder** caused by a partial or complete deficiency of the enzyme **HGPRT**. - This deficiency leads to an accumulation of **uric acid** and neurological dysfunction, including self-mutilation and dystonia. *Adenine phosphoribosyltransferase (APRT)* - Deficiency of **APRT** primarily leads to the formation of **2,8-dihydroxyadenine stones** in the urinary tract, not Lesch-Nyhan syndrome. - While it is also a salvage pathway enzyme for purines, its deficiency does not result in the severe neurological and behavioral symptoms seen in Lesch-Nyhan. *Xanthine oxidase* - **Xanthine oxidase** is involved in the catabolism of purines, converting **hypoxanthine** to **xanthine** and then to **uric acid**. - Its deficiency (e.g., in xanthinuria) leads to stones composed of **xanthine**, not the neurological and metabolic disturbances of Lesch-Nyhan. *Adenosine deaminase (ADA)* - Deficiency of **ADA** causes **severe combined immunodeficiency (SCID)**, characterized by profound T-cell and B-cell dysfunction. - This enzyme is crucial for the metabolism of adenosine and deoxyadenosine, and its absence leads to lymphocyte toxicity, not the symptoms of Lesch-Nyhan syndrome.

Question 695: In Wilson’s disease, which of the following substances is excreted in lower amounts in the urine?

A. Phosphotyrosine
B. Methyl- Histidine (Correct Answer)
C. Phosphorus
D. Serine

Explanation: **Important Note:** In Wilson's disease with Fanconi syndrome (proximal renal tubular dysfunction), most substances show **increased** urinary excretion, not decreased. This question appears to test knowledge of what is NOT characteristically elevated. ***Methyl-Histidine*** (Most appropriate answer) - **Methyl-histidine** (3-methylhistidine) is a marker of **muscle protein breakdown** and is not directly affected by the renal tubular dysfunction in Wilson's disease - Unlike phosphate, amino acids, and glucose which are pathologically increased in urine due to Fanconi syndrome, methyl-histidine excretion remains **normal** or is unrelated to copper-induced renal damage - This represents the substance least affected by Wilson's disease pathology *Phosphorus* (Actually INCREASED, not decreased) - **Medically incorrect as stated**: Phosphorus (phosphate) is actually **INCREASED** in urine in Wilson's disease, not decreased - Fanconi syndrome causes **renal phosphate wasting**, leading to hyperphosphaturia and resultant hypophosphatemia - This is a characteristic feature of proximal tubular dysfunction *Serine* (INCREASED due to aminoaciduria) - **Serine** and other amino acids show **generalized aminoaciduria** in Wilson's disease due to impaired proximal tubular reabsorption - Urinary serine is **elevated**, not decreased *Phosphotyrosine* - A phosphorylated amino acid involved in cell signaling, not routinely measured clinically - Not characteristically implicated in Wilson's disease urinary patterns

Question 696: Which single gene disorder does not follow Mendelian inheritance?

A. Fragile X-syndrome (Correct Answer)
B. Retinoblastoma (hereditary)
C. Huntington's disease
D. Sickle cell disease

Explanation: ***Fragile X-syndrome*** - While Fragile X-syndrome follows **X-linked dominant inheritance** (a Mendelian pattern), it exhibits **atypical features** that distinguish it from classic Mendelian disorders - The **trinucleotide repeat expansion** (CGG repeats in *FMR1* gene) leads to **anticipation** - increasing severity across generations - Shows **reduced penetrance** - premutation carriers may be asymptomatic, and the phenotype depends on repeat number, not just gene presence - Among the given options, this represents the **most modified form of Mendelian inheritance** *Huntington's disease* - Classic **autosomal dominant** disorder with CAG trinucleotide repeat expansion in the *HTT* gene - Follows typical Mendelian inheritance: affected parent has 50% chance of passing the mutation to each child - Though it shows anticipation, the inheritance pattern itself is straightforward Mendelian *Retinoblastoma (hereditary)* - Clear **autosomal dominant** inheritance pattern due to *RB1* gene mutation - Follows Mendelian principles with high penetrance (~90%) - The "two-hit hypothesis" explains tumor development but doesn't alter the Mendelian inheritance pattern *Sickle cell disease* - Textbook **autosomal recessive** disorder caused by a point mutation in the beta-globin gene (HbS) - Perfectly follows Mendelian laws: requires two copies of the mutant allele for disease manifestation - Heterozygotes (carriers) show sickle cell trait, demonstrating co-dominance at the molecular level

Question 697: Fish odor syndrome is caused by deficiency of which enzyme?

A. Fumarylacetoacetate hydrolase
B. Methane monooxygenase
C. D-amino acid oxidase
D. Flavin-containing monooxygenase 3 (FMO3) (Correct Answer)

Explanation: ***Flavin-containing monooxygenase 3 (FMO3)*** - **Trimethylaminuria**, or "fish odor syndrome," is caused by a genetic defect in the **FMO3 enzyme**. - This enzyme is responsible for converting **trimethylamine (TMA)**, a breakdown product of certain foods, into an odorless form, **trimethylamine N-oxide (TMAO)**. *Fumarylacetoacetate hydrolase* - Deficiency in this enzyme causes **Tyrosinemia type 1**, a metabolic disorder affecting tyrosine metabolism. - It leads to severe liver disease, kidney dysfunction, and neurological crises, not a fishy body odor. *Methane monooxygenase* - This enzyme is found in certain **bacteria** (methanotrophs) and is involved in the metabolism of methane. - It is not present in humans and has no known link to human metabolic disorders like fish odor syndrome. *D-amino acid oxidase* - This enzyme is involved in the metabolism of **D-amino acids**, which are less common in mammals but found in bacteria and some foods. - Its deficiency is not associated with trimethylaminuria or a fishy body odor.

Question 698: Menkes disease is associated with which enzyme deficiency?

A. Tyrosinase deficiency
B. Ceruloplasmin deficiency
C. Dopamine beta-hydroxylase deficiency
D. Copper-transporting ATPase deficiency (Correct Answer)

Explanation: ***Copper-transporting ATPase deficiency*** - **Menkes disease** (also known as Menkes kinky hair syndrome) is an **X-linked recessive disorder** caused by mutations in the **ATP7A gene**, which encodes the **copper-transporting P-type ATPase**. - This deficiency leads to impaired intestinal absorption and cellular transport of copper, resulting in **copper deficiency** in various tissues despite normal or even elevated levels in the intestinal lumen and some other cell types. *Tyrosinase deficiency* - **Tyrosinase** is an enzyme involved in the synthesis of **melanin**, and its deficiency is characteristic of certain forms of **albinism**, not Menkes disease. - Albinism is primarily characterized by hypopigmentation of skin, hair, and eyes due to reduced melanin production. *Ceruloplasmin deficiency* - **Ceruloplasmin** is a copper-carrying protein, and its deficiency is a hallmark of **Wilson's disease**, another disorder of copper metabolism, but it results from mutations in the ATP7B gene (which encodes a different copper-transporting ATPase). - Wilson's disease leads to copper accumulation in tissues like the liver and brain, contrasting with the copper deficiency seen in Menkes disease. *Dopamine beta-hydroxylase deficiency* - **Dopamine beta-hydroxylase** is an enzyme responsible for converting **dopamine to norepinephrine**. - Its deficiency results in an inability to synthesize norepinephrine and epinephrine, leading to symptoms like **orthostatic hypotension** and ptosis, unrelated to copper metabolism.

Question 699: Which disorder is most characteristically linked to the X chromosome?

A. X-linked color vision deficiency (Correct Answer)
B. Beta-thalassemia
C. Klinefelter syndrome
D. Retinitis pigmentosa

Explanation: ***X-linked color vision deficiency*** - This condition is **classically inherited in an X-linked recessive pattern**, meaning the gene responsible for the disorder is located on the **X chromosome**. - Males are more frequently affected because they have only one X chromosome, so a single copy of the mutated gene is sufficient to cause the condition. - This is the **prototypical example** of X-linked recessive inheritance. *Beta-thalassemia* - This is an **autosomal recessive** blood disorder, meaning the genes responsible are located on **non-sex chromosomes** (autosomes). - Both parents must carry the mutated gene for a child to inherit the disorder. *Klinefelter syndrome* - This is a **chromosomal aneuploidy** resulting from the presence of an **extra X chromosome** in males (47,XXY karyotype). - While it involves the X chromosome, it is a **numerical chromosomal abnormality** rather than a genetic disorder linked to a specific gene on the X chromosome that is passed down in a typical X-linked inheritance pattern. *Retinitis pigmentosa* - This is a group of **inherited eye diseases** that can be inherited in **multiple patterns**, including autosomal dominant, autosomal recessive, and X-linked recessive. - While some forms (~10-20%) are X-linked, it is **not exclusively or primarily** an X-linked disorder, and other options (like X-linked color vision deficiency) are more **characteristically** known for their X-linked inheritance.

Question 700: Which of the following is a marker for neural tube defects?

A. ↑Pseudocholinesterase
B. ↑Acetylcholinesterase (Correct Answer)
C. ↑Alpha-fetoprotein (AFP)
D. ↑Alkaline phosphatase

Explanation: ***↑Acetylcholinesterase*** - Elevated **acetylcholinesterase (AChE)** in amniotic fluid is a highly specific marker for **open neural tube defects (NTDs)**. - AChE is normally confined to nervous tissue; its presence in amniotic fluid suggests leakage from exposed fetal neural tissue. - AChE provides higher **specificity** than AFP for confirming open NTDs. *↑Alkaline phosphatase* - Elevated **alkaline phosphatase (ALP)** in amniotic fluid is associated with abnormalities like **omphalocele** and **gastroschisis**, but not specifically NTDs. - ALP levels can also be elevated in other conditions and are not a primary marker for neural tube defects. *↑Pseudocholinesterase* - **Pseudocholinesterase (butyrylcholinesterase)** is found in the liver, plasma, and other tissues, and its elevation is not a specific marker for neural tube defects. - It is sometimes used as a marker for liver function or exposure to certain toxins, not for fetal malformations. *↑Alpha-fetoprotein (AFP)* - While **AFP** is elevated in maternal serum and amniotic fluid with open NTDs, it is a **screening marker** with lower specificity. - AFP elevation can occur in other conditions (abdominal wall defects, multiple gestation, fetal demise), making it less specific than acetylcholinesterase for confirming NTDs.

Practice by Chapter

Single Gene Disorders

Practice Questions

Biochemical Diagnosis of Genetic Disorders

Practice Questions

Inborn Errors of Metabolism

Practice Questions

Lysosomal Storage Diseases

Practice Questions

Glycogen Storage Diseases

Practice Questions

Disorders of Lipoprotein Metabolism

Practice Questions

Disorders of Purine and Pyrimidine Metabolism

Practice Questions

Hemoglobinopathies

Practice Questions

Porphyrias

Practice Questions

Biochemical Markers for Disease Diagnosis

Practice Questions

Newborn Screening for Genetic Disorders

Practice Questions

Enzyme Replacement Therapy

Practice Questions

Want unlimited practice?

Get full access to all questions, explanations, and performance tracking.

Start For Free