Genetic Disorders and Biochemical Pathology — MCQs

An 8-month-old baby girl had normal growth and development for the first few months, but then progressively deteriorated with deafness, blindness, atrophied muscles, inability to swallow, and seizures. Early on in the diagnosis of the child, it was noticed that a cherry-red macula was present in both eyes. Considering the child in the above case, measurement of which one of the following would enable one to determine whether the mutation was in the hexA or hexB gene?

Q758

Enzyme deficiency in Farber disease is:

Q759

Tay-Sachs disease is due to a deficiency of which enzyme?

Q760

Which of the following statements regarding phenylketonuria (PKU) is false?

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

Question 751: Gaucher's disease is:

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

Explanation: ***Autosomal recessive inheritance*** - **Gaucher's disease** is caused by a deficiency of the enzyme **glucocerebrosidase**, leading to the accumulation of glucocerebroside in macrophages. - This genetic disorder requires two copies of the defective gene (one from each parent) to manifest, which is characteristic of **autosomal recessive inheritance**. *Autosomal dominant inheritance* - In **autosomal dominant inheritance**, only one copy of the defective gene is needed for the disease to occur, which is not the case for Gaucher's disease. - Affected individuals usually have at least one affected parent, and there is a 50% chance of passing the condition to offspring. *X-linked recessive inheritance* - **X-linked recessive inheritance** primarily affects males, as the gene is located on the X chromosome. - Females are typically carriers and are less commonly affected, which does not describe the inheritance pattern of Gaucher's disease. *X-linked dominant inheritance* - **X-linked dominant inheritance** means the disease can affect both males and females, but females are typically more mildly affected. - All daughters of an affected father will inherit the condition, which is not consistent with Gaucher's disease.

Question 752: Which of the following porphyrias is not inherited as an autosomal dominant disorder?

A. Porphyria Cutanea Tarda
B. Hereditary Coproporphyria
C. Acute Intermittent Porphyria
D. Congenital Erythropoietic Porphyria (Correct Answer)

Explanation: ***Congenital Erythropoietic Porphyria*** - This porphyria is inherited in an **autosomal recessive** pattern, meaning two copies of the defective gene (one from each parent) are required for the disease to manifest. - It results from a deficiency in **uroporphyrinogen III synthase (URO-synthase)**, leading to the accumulation of uroporphyrinogen I and coproporphyrinogen I isomers. *Acute Intermittent Porphyria* - This is an **autosomal dominant** disorder caused by a deficiency in **hydroxymethylbilane synthase (HMBS)**, also known as porphyrobilinogen deaminase (PBG deaminase). - It primarily affects the nervous system, leading to acute neurovisceral attacks. *Porphyria Cutanea Tarda* - This is **primarily sporadic (acquired)** in about 80% of cases, often associated with hepatic iron overload, alcohol use, hepatitis C, or estrogen use. - Only about 20% of cases are familial with **autosomal dominant** inheritance pattern. - It is caused by a deficiency in **uroporphyrinogen decarboxylase (UROD)**, leading to photosensitivity due to accumulated porphyrins in the skin. *Hereditary Coproporphyria* - This is an **autosomal dominant** disorder caused by a deficiency in **coproporphyrinogen oxidase (CPOX)**. - It can present with both neurovisceral attacks and photosensitivity, depending on the accumulated porphyrins.

Question 753: A child with intellectual disability presenting with hoarseness, frequent dermatitis, and skeletal deformities was diagnosed to have Farber's disease. Which enzyme is deficient in this child?

A. Ceramidase (Correct Answer)
B. Arylsulfatase A
C. Beta-Glucosidase
D. Sphingomyelinase

Explanation: ***Correct Answer: Ceramidase*** - Farber's disease, also known as **Farber lipogranulomatosis** or **acid ceramidase deficiency**, is caused by a deficiency in the enzyme **acid ceramidase** - This enzyme is crucial for the breakdown of **ceramide**, leading to its accumulation in various tissues - Accumulation results in the characteristic symptoms: **hoarseness** (from laryngeal involvement), **dermatitis** (subcutaneous nodules), and **skeletal deformities** (joint contractures) - This is a rare autosomal recessive lysosomal storage disorder *Incorrect: Arylsulfatase A* - Deficiency causes **metachromatic leukodystrophy**, a lysosomal storage disorder affecting the nervous system - Presents with progressive neurological deterioration, peripheral neuropathy, and developmental regression - Does not present with the specific constellation of **hoarseness**, **dermatitis**, and **skeletal deformities** seen in Farber's disease *Incorrect: Beta-Glucosidase* - Deficiency in **beta-glucosidase** (glucocerebrosidase) causes **Gaucher disease** - Characterized by **hepatosplenomegaly**, **anemia**, **thrombocytopenia**, and **bone complications** (bone pain, fractures) - The clinical picture differs from Farber's disease presentation *Incorrect: Sphingomyelinase* - Deficiency causes **Niemann-Pick disease** (Types A and B) - Characterized by **sphingomyelin accumulation**, **hepatosplenomegaly**, and **neurodegenerative symptoms** (Type A) - Symptoms differ from the **hoarseness**, **dermatitis**, and **skeletal deformities** characteristic of Farber's disease

Question 754: The PRSS1 gene is located on?

A. Chr 20q
B. Chr 17p
C. Chr 7q (Correct Answer)
D. Chr 1p

Explanation: ***Chr 7q*** - The **PRSS1 gene**, which encodes for **cationic trypsinogen**, is located on the long arm (**q arm**) of **chromosome 7**. - Mutations in this gene are strongly associated with **hereditary pancreatitis**. *Chr 20q* - This chromosome location is associated with various other genes and diseases, but not typically with the **PRSS1 gene** or **hereditary pancreatitis**. - For example, genes related to **diabetes** and **obesity** are found on chromosome 20. *Chr 17p* - This region is known for containing several important genes, such as **TP53** (a tumor suppressor gene), but it is not the location for **PRSS1**. - Deletions or mutations in **17p** are linked to conditions like **Li-Fraumeni syndrome**. *Chr 1p* - **Chromosome 1**, specifically the short arm (**p arm**), contains a large number of genes and is implicated in many diseases, including certain **cancers**. - However, the **PRSS1 gene** is not found at this chromosomal location.

Question 755: Which of the following is a genetic disorder that does not primarily affect ion channels?

A. Cystic fibrosis
B. Liddle's syndrome
C. Hypokalemic periodic paralysis
D. Tay-Sachs disease (Correct Answer)

Explanation: ***Cystic fibrosis*** - Primarily caused by mutations in the **CFTR gene**, which encodes a **chloride channel**, but it is not classified as a classic channelopathy. - The disease mainly affects **mucus production** rather than direct dysfunction of ion channels in the traditional sense. [1] *Hypokalemic periodic paralysis* - This condition is directly related to **ion channel dysfunction**, specifically affecting **sodium channels** in muscle cells. - It causes episodic **muscle weakness** and hypokalemia due to improper ion transport. *Liddle's syndrome* - A genetic disorder resulting from mutations affecting **epithelial sodium channels**, leading to **hypertension**. - It exemplifies classic channelopathy by causing dysregulation of sodium reabsorption in the kidneys. *Tay-sach's disease* - A ***gangliosidosis*** caused by a deficiency in the enzyme **Hexosaminidase A**, rather than ion channel dysfunction. - It results in the accumulation of **GM2 gangliosides** leading to neurological degeneration, not affecting ion channels directly. **References:** [1] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. (Basic Pathology) introduces the student to key general principles of pathology, both as a medical science and as a clinical activity with a vital role in patient care. Part 2 (Disease Mechanisms) provides fundamental knowledge about the cellular and molecular processes involved in diseases, providing the rationale for their treatment. Part 3 (Systematic Pathology) deals in detail with specific diseases, with emphasis on the clinically important aspects., pp. 120-122.

Question 756: A 34-year-old, G1P0, presents for genetic counseling at 12 weeks' gestation. The patient has two sisters and a brother; her father has hemophilia. Her siblings are not affected, but she has a nephew who is affected. What is the inheritance pattern of this disorder?

A. X-linked inheritance (Correct Answer)
B. Autosomal recessive
C. Mitochondrial inheritance
D. Multifactorial inheritance

Explanation: ***X-linked inheritance*** - Hemophilia is an **X-linked recessive disorder** - An affected father passes his X chromosome mutation to **all daughters**, making them **obligate carriers** (not affected but carry the gene) - The affected nephew (son of patient's sister) confirms the patient's sister is a carrier who passed the affected X chromosome to her son - Classic pattern: affected males, carrier females, skips generations through female carriers *Autosomal recessive* - Would require both parents to be carriers for offspring to be affected - An affected father would pass one mutant allele to all children, but this wouldn't make daughters obligate carriers unless mother also carried the gene - Pattern of father → carrier daughter → affected grandson is not typical of autosomal recessive inheritance *Mitochondrial inheritance* - Only transmitted from mother to **all children** regardless of gender - Affected father **cannot** pass mitochondrial disorders to offspring - Would show maternal transmission pattern with all children of affected mothers being affected *Multifactorial inheritance* - Involves combination of multiple genes and environmental factors - Does not follow clear Mendelian pattern - The distinct single-gene pattern (affected father, carrier daughters, affected male grandchild) indicates X-linked recessive, not multifactorial

Question 757: An 8-month-old baby girl had normal growth and development for the first few months, but then progressively deteriorated with deafness, blindness, atrophied muscles, inability to swallow, and seizures. Early on in the diagnosis of the child, it was noticed that a cherry-red macula was present in both eyes. Considering the child in the above case, measurement of which one of the following would enable one to determine whether the mutation was in the hexA or hexB gene?

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

Explanation: ***Globoside*** - A mutation in the **hexA** gene leads to **Tay-Sachs disease** (deficient **HexA**), characterized by the accumulation of **GM2 ganglioside only**. - A mutation in the **hexB** gene leads to **Sandhoff disease** (deficient **HexB**), which results in the accumulation of **both GM2 ganglioside and globoside**, as **HexB** is crucial for the breakdown of **globosides**. - **Measuring globoside levels would differentiate between these two conditions** - elevated in Sandhoff, normal in Tay-Sachs. *GM1* - **GM1 ganglioside** accumulates in **GM1 gangliosidosis**, caused by a deficiency in **beta-galactosidase**, not hexosaminidase A or B. - Clinical features of **GM1 gangliosidosis** overlap but differ from Tay-Sachs or Sandhoff, and it's not directly affected by **hexA** or **hexB** mutations. *GM2* - **GM2 ganglioside** accumulates in **both Tay-Sachs disease** (due to **HexA** deficiency) and **Sandhoff disease** (due to **HexB** deficiency). - Measuring **GM2** alone would confirm a **hexosaminidase deficiency** but **would not differentiate** between a **hexA** (Tay-Sachs) or **hexB** (Sandhoff) mutation, as it is elevated in both conditions. *Glucocerebroside* - **Glucocerebroside** accumulates in **Gaucher disease**, which is caused by a deficiency in the enzyme **glucocerebrosidase**. - This condition has a distinct clinical presentation and is not related to mutations in the **hexA** or **hexB** genes.

Question 758: Enzyme deficiency in Farber disease is:

A. Arylsulfatase A
B. Sphingomyelinase
C. Ceramidase (Correct Answer)
D. Hexosaminidase A

Explanation: ***Ceramidase*** - Farber disease, also known as **Farber lipogranulomatosis** or **Farber's disease**, is an autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme **acid ceramidase**. - This deficiency leads to the accumulation of **ceramide** in various tissues, causing granulomatous lesions, joint deformities, and neurological symptoms. *Arylsulfatase A* - Deficiency of **arylsulfatase A** is associated with **metachromatic leukodystrophy**, a lysosomal storage disorder affecting the nervous system. - This enzyme is crucial for the breakdown of **sulfatides**, not ceramide. *Sphingomyelinase* - A deficiency in **sphingomyelinase** is the hallmark of **Niemann-Pick disease**, specifically types A and B. - This enzyme is responsible for breaking down **sphingomyelin**, leading to its accumulation in organs like the liver, spleen, and brain. *Hexosaminidase A* - A deficiency in **hexosaminidase A** is the cause of **Tay-Sachs disease**, a severe neurodegenerative disorder. - This enzyme is essential for the metabolism of **GM2 ganglioside**, which accumulates in neurons in affected individuals.

Question 759: Tay-Sachs disease is due to a deficiency of which enzyme?

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

Explanation: ***Hexosaminidase A*** - **Tay-Sachs disease** is caused by a genetic deficiency in the lysosomal enzyme **hexosaminidase A (HexA)**. - This deficiency leads to the accumulation of **GM2 ganglioside** in neuronal cells, particularly in the brain, causing progressive neurodegeneration. *Hexosaminidase B* - A deficiency in **hexosaminidase B** is associated with **Sandhoff disease**, a lysosomal storage disorder similar to Tay-Sachs but typically more severe. - While HexA is composed of alpha and beta subunits, a deficiency specifically in the beta subunit is characteristic of Sandhoff disease. *α-galactosidase* - A deficiency in **α-galactosidase** is responsible for **Fabry disease**, an X-linked lysosomal storage disorder. - It leads to the accumulation of **globotriaosylceramide (Gb3)**, primarily affecting the kidneys, heart, and nervous system, and does not present with the neurological symptoms of Tay-Sachs. *Sphingomyelinase* - A deficiency in **sphingomyelinase** causes **Niemann-Pick disease (Type A and B)**, another lysosomal storage disorder. - This leads to the accumulation of **sphingomyelin** in various organs, resulting in hepatosplenomegaly, neurodegeneration (in Type A), and lung disease, distinct from Tay-Sachs.

Question 760: Which of the following statements regarding phenylketonuria (PKU) is false?

A. Blood phenyl alanine level >20 mg/dl causes severe disease
B. Neurological symptoms are due to deficiency of phenylalanine hydroxylase. (Correct Answer)
C. Method of choice for screening is blood phenylalanine by Guthrie's test.
D. PKU is caused by a deficiency of phenylalanine hydroxylase.

Explanation: ***Neurological symptoms are due to deficiency of phenylalanine hydroxylase.*** - This statement is **FALSE** - it confuses the cause with the mechanism. - Neurological symptoms in PKU are caused by the **accumulation of phenylalanine and its toxic metabolites** (such as phenylpyruvate, phenyllactate, and phenylacetate) in the brain, not directly by the enzyme deficiency itself. - The deficiency of **phenylalanine hydroxylase** is the underlying cause, but the **toxic buildup** is what damages the developing brain, leading to intellectual disability, seizures, and behavioral problems. *Blood phenyl alanine level >20 mg/dl causes severe disease* - This statement is **TRUE**. - Blood phenylalanine levels **>20 mg/dL** are diagnostic of **classical PKU**, which causes severe disease if untreated. - Normal phenylalanine levels are 1-2 mg/dL; levels >20 mg/dL require strict dietary management to prevent neurological damage. *Method of choice for screening is blood phenylalanine by Guthrie's test.* - This statement is **TRUE** in the traditional context taught for medical exams. - The **Guthrie bacterial inhibition assay** measures blood phenylalanine from a heel prick and has been the standard newborn screening method for decades. - While modern laboratories increasingly use **tandem mass spectrometry (MS/MS)**, the Guthrie test remains a validated and widely taught screening method. *PKU is caused by a deficiency of phenylalanine hydroxylase.* - This statement is **TRUE**. - **Phenylketonuria (PKU)** is an autosomal recessive disorder caused by mutations in the **PAH gene**, leading to deficiency of the enzyme **phenylalanine hydroxylase**. - This enzyme normally converts phenylalanine to tyrosine; its absence leads to phenylalanine accumulation.

Practice by Chapter

Single Gene Disorders

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Biochemical Diagnosis of Genetic Disorders

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Inborn Errors of Metabolism

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Lysosomal Storage Diseases

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Glycogen Storage Diseases

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Disorders of Lipoprotein Metabolism

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Disorders of Purine and Pyrimidine Metabolism

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Hemoglobinopathies

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Porphyrias

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Biochemical Markers for Disease Diagnosis

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Newborn Screening for Genetic Disorders

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Enzyme Replacement Therapy

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