Genetic Disorders and Biochemical Pathology Practice Questions

Q: A family pedigree chart is given below. Identify the mode of inheritance of this condition.

Autosomal dominant. ***Autosomal dominant*** - The trait is observed in **every generation** (I, II), which is a hallmark of dominant inheritance, as it does not skip generations. - The presence of **male-to-male transmission** (individual 4 to individual 9) definitively rules out X-linked inheritance. Additionally, affected parents (1 and 2) have an unaffected child (7), indicating the parents are likely heterozygous. *Autosomal recessive* - This is ruled out because two affected parents (1 and 2) have an unaffected child (7). If the trait were recessive, all children of two affected parents **must also be affected**. - Typically, autosomal recessive traits **skip generations**, with carriers being phenotypically normal, which is not the pattern seen here. *X-linked recessive* - An affected mother (individual 2) must pass the recessive allele to **all of her sons**. However, her son (individual 7) is unaffected, which contradicts this inheritance pattern. - The presence of **male-to-male transmission** (4 to 9) is impossible in X-linked inheritance, as fathers pass their Y chromosome to sons, not the X chromosome carrying the trait. *X-linked dominant* - An affected father must pass the trait to **all of his daughters**. In this pedigree, the affected father (individual 4) has an unaffected daughter (individual 8), which rules out this mode. - Similarly, another affected father (individual 9) has an unaffected daughter (individual 11), further disproving this pattern.

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

Autosomal dominant. ***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 a X a **) 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.

Q: The pedigree diagram of a family is shown below. Affected individuals present with progressive external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects. Based on the pedigree and clinical features, what is the most likely diagnosis?

Kearns-Sayre Syndrome. ***Kearns-Sayre Syndrome*** * Kearns-Sayre Syndrome (KSS) is a **mitochondrial disorder** caused by large-scale deletions in **mtDNA** (mtDNA deletion syndrome). * The classic triad of KSS is **progressive external ophthalmoplegia (PEO)**, **pigmentary retinopathy**, and onset before age 20, often associated with **cardiac conduction defects** and cerebellar ataxia, matching the clinical presentation. *Duchenne Muscular Dystrophy* * DMD is an **X-linked recessive** disorder, which would show mother-to-son transmission, but not father-to-son transmission. The pedigree shows affected males having affected children (both male and female), inconsistent with X-linked inheritance. * The primary features are **progressive proximal muscle weakness** and Gower's sign, not the characteristic ophthalmoplegia, retinopathy, and heart block of KSS. *Friedreich Ataxia* * Friedreich ataxia is an **autosomal recessive** disorder, which would typically skip generations and mainly present in siblings of unaffected parents. This is inconsistent with the clear mother-to-child transmission seen in the pedigree. * The key features are **ataxia**, **dysarthria**, and **loss of vibratory sense**, not primarily ophthalmoplegia and pigmentary retinopathy. *Myotonic Dystrophy* * Myotonic dystrophy (DM1) is an **autosomal dominant** disorder, consistent with the vertical transmission, but the genetic defect is an **unstable trinucleotide repeat (CTG)**. While it can involve **cardiac conduction defects**, the primary clinical feature is **myotonia** (inability to quickly relax muscles) and facial weakness. * The absence of myotonia and the distinct presentation of PEO and pigmentary retinopathy make KSS a better fit than myotonic dystrophy.

Q: A 6-month-old infant presents with recurrent infections and failure to thrive. Laboratory investigations reveal a deficiency of adenosine deaminase (ADA). Which of the following immunodeficiency disorders is most likely associated?

Severe Combined Immunodeficiency (SCID). ***Severe Combined Immunodeficiency (SCID)*** - **Adenosine deaminase (ADA) deficiency** is a classic autosomal recessive cause of SCID, resulting in accumulation of toxic metabolites like **dATP**. - These toxic metabolites destroy both **T and B lymphocytes**, leading to profound lymphopenia and the severe clinical picture of recurrent infections and **failure to thrive**. *Hypogammaglobulinemia* - This term generally refers to primary **B-cell intrinsic defects** leading to reduced antibody levels (e.g., X-linked agammaglobulinemia or CVID). - While it causes recurrent infections, the underlying genetic defect is specific to B-cell development or function, not **ADA deficiency** affecting both T and B cells profoundly. *DiGeorge Syndrome* - This syndrome is caused by a defect in the 3rd and 4th pharyngeal pouches, often due to **22q11 microdeletion**, resulting in **thymic aplasia** (T-cell deficiency). - Clinical presentation involves the triad of T-cell defect, **cardiac anomalies** (conotruncal defects), and **hypocalcemia** (parathyroid hypoplasia), not ADA deficiency. *Wiskott-Aldrich Syndrome* - This is an X-linked disorder defined by the classic triad of **eczema**, immunodeficiency, and **thrombocytopenia** (small platelets). - The mutation affects the **WASP gene**, leading to defective cytoskeleton function in hematopoietic cells, which is unrelated to ADA enzymatic deficiency.

Q: 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?

Dermatan sulfate + Heparan sulfate. ***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.

Q: Which of the following is a mitochondrial inheritance disorder?

Kearns-Sayre syndrome. ***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.

Q: Identify the pattern of inheritance shown below.

Mitochondrial inheritance. ***Mitochondrial inheritance*** - This pedigree shows **maternal inheritance**, where all children of an affected mother are affected, but none of the children of an affected father are affected. This is characteristic of mitochondrial inheritance as mitochondrial DNA is exclusively inherited from the mother. - The trait is passed from the **affected mother** to all her offspring regardless of sex. *X linked Dominant inheritance* - In X-linked dominant inheritance, affected fathers pass the trait to **all their daughters**, and no sons. This pattern is not observed here, as affected fathers do not pass the trait to any of their children. - Affected mothers can pass the trait to both sons and daughters, but affected males also pass to all daughters, which is absent. *Y linked Inheritance* - Y-linked inheritance would show transmission only from **father to son**. This pedigree shows affected females as well, and affected fathers do not pass the trait to their sons in the observed pattern. - No instances of father-to-son transmission are observed in the parts of the pedigree where the father is affected. *X linked Recessive inheritance* - X-linked recessive inheritance typically shows more affected **males than females**, and affected fathers cannot pass the trait to their sons. Daughters of affected fathers are carriers if the mother is not affected. - There is no transmission from affected fathers to any of their offspring in the observed pedigree.

Q: During evaluation of a child with intellectual disability following findings were noted. These point to deficiency of?

Alpha-L-Iduronidase. ***Alpha-L-Iduronidase*** - The image shows **coarse facial features**, **corneal clouding**, and an **umbilical hernia**, which are characteristic signs of Hurler syndrome (MPS I). - Hurler syndrome is caused by a deficiency of the enzyme **alpha-L-iduronidase**, leading to the accumulation of dermatan sulfate and heparan sulfate. *L-sulfoiduronate sulfatase* - Deficiency of **L-sulfoiduronate sulfatase** causes Hunter syndrome (MPS II). - Hunter syndrome spares the **cornea** (no corneal clouding) and has a different clinical presentation, including X-linked inheritance. *Heparan sulfate sulfamidase* - A deficiency in **heparan sulfate sulfamidase** leads to Sanfilippo syndrome (MPS IIIA). - While Sanfilippo syndrome involves severe neurodegeneration, it typically lacks the prominent **skeletal abnormalities** and **corneal clouding** seen in Hurler syndrome. *N-acetylgalactosamine-4-sulfatase* - Deficiency of **N-acetylgalactosamine-4-sulfatase** causes Maroteaux-Lamy syndrome (MPS VI). - Maroteaux-Lamy syndrome is characterized by severe skeletal involvement and corneal clouding but generally has preservation of **intellectual function**, unlike Hurler syndrome.

Q: A 10-month-old child with coarse facies is referred for developmental delay. On examination, hepatosplenomegaly was noted. WBC N-acetylglucosamine-1-phosphotransferase activity was absent. The X-ray is shown below. What is the diagnosis?

I cell disease. ***I cell disease*** - **I-cell disease** (Mucolipidosis II) is characterized by **coarse facial features**, developmental delay, hepatosplenomegaly, and **skeletal abnormalities** (dysostosis multiplex) seen on X-ray, which are consistent with the image. - The absence of **N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase)** activity leads to misrouting of lysosomal enzymes, resulting in accumulation of mucolipids within cells. *MPS type II* - **MPS type II** (Hunter syndrome) also presents with coarse facies, developmental delay, and hepatosplenomegaly, and can show skeletal abnormalities. - However, the enzymatic defect is in **iduronate sulfatase**, not GlcNAc-1-phosphotransferase, and the clinical course tends to be slightly milder than I-cell disease, particularly in early infancy. *Proteus syndrome* - **Proteus syndrome** is characterized by **overgrowth of tissues**, asymmetric growth, and various tumors, not by the specific metabolic defect or typical pattern of skeletal changes described. - It does not involve absent GlcNAc-1-phosphotransferase activity. *Larsen syndrome* - **Larsen syndrome** primarily involves **skeletal abnormalities**, such as joint dislocations (especially knees, hips, and elbows), flattened facial appearance, and clubfoot. - It does not feature the same metabolic defect (absent GlcNAc-1-phosphotransferase activity) or the prominent coarse facial features and hepatosplenomegaly seen in the patient.

Question 1

A family pedigree chart is given below. Identify the mode of inheritance of this condition.

Accepted Answer

Autosomal dominant

Answer

X-linked dominant

Answer

Autosomal recessive

Answer

X-linked recessive

Question 2

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

Accepted Answer

Autosomal dominant

Answer

Autosomal recessive

Answer

X-linked recessive

Answer

X-linked dominant

Question 3

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

Accepted Answer

Direct bilirubin normal, indirect bilirubin increased, and urobilinogen normal

Answer

Indirect bilirubin increased, direct bilirubin normal, and raised urine urobilinogen

Answer

Direct bilirubin increased, indirect bilirubin decreased, and urine urobilinogen/urobilin increased

Answer

Raised direct bilirubin, normal indirect bilirubin, and absent urine bilirubin

Question 4

The pedigree diagram of a family is shown below. Affected individuals present with progressive external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects. Based on the pedigree and clinical features, what is the most likely diagnosis?

Accepted Answer

Kearns-Sayre Syndrome

Answer

Duchenne Muscular Dystrophy

Answer

Friedreich Ataxia

Answer

Myotonic Dystrophy

Question 5

A 6-month-old infant presents with recurrent infections and failure to thrive. Laboratory investigations reveal a deficiency of adenosine deaminase (ADA). Which of the following immunodeficiency disorders is most likely associated?

Accepted Answer

Severe Combined Immunodeficiency (SCID)

Answer

Hypogammaglobulinemia

Answer

Wiskott-Aldrich Syndrome

Answer

DiGeorge Syndrome

Question 6

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?

Accepted Answer

Dermatan sulfate + Heparan sulfate

Answer

Only Dermatan sulfate

Answer

Heparan sulfate + Chondroitin sulfate

Answer

Dermatan sulfate + Chondroitin sulfate

Question 7

Which of the following is a mitochondrial inheritance disorder?

Accepted Answer

Kearns-Sayre syndrome

Answer

Achondroplasia

Answer

Cystic fibrosis

Answer

Williams syndrome

Question 8

Identify the pattern of inheritance shown below.

Accepted Answer

Mitochondrial inheritance

Answer

X linked Dominant inheritance

Answer

Y linked Inheritance

Answer

X linked Recessive inheritance

Question 9

During evaluation of a child with intellectual disability following findings were noted. These point to deficiency of?

Accepted Answer

Alpha-L-Iduronidase

Answer

L-sulfoiduronate sulfatase

Answer

Heparan sulfate sulfamidase

Answer

N-acetylgalactosamine-4-sulfatase

Question 10

A 10-month-old child with coarse facies is referred for developmental delay. On examination, hepatosplenomegaly was noted. WBC N-acetylglucosamine-1-phosphotransferase activity was absent. The X-ray is shown below. What is the diagnosis?

Accepted Answer

I cell disease

Answer

MPS type II

Answer

Proteus syndrome

Answer

Larsen syndrome

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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