Genetic Disorders and Biochemical Pathology Practice Questions

Q: Which one of the following diseases is classified as an autosomal dominant disorder?

Maturity onset diabetes of the young. ***Maturity onset diabetes of the young*** - **Maturity onset diabetes of the young (MODY)** is a genetically heterogeneous group of single-gene disorders characterized by beta-cell dysfunction and impaired insulin secretion, typically inherited in an **autosomal dominant pattern** [1]. - A single copy of the mutated gene is sufficient to cause the condition, leading to diabetes usually before the age of 25, often without obesity or autoantibodies [1]. *Hemochromatosis* - **Hemochromatosis** is typically inherited in an **autosomal recessive pattern**, meaning two copies of the mutated gene (e.g., *HFE* gene) are required for the disease to manifest. - It leads to excessive iron absorption and tissue iron overload. *Phenylketonuria* - **Phenylketonuria (PKU)** is an **autosomal recessive disorder** caused by a deficiency in the enzyme **phenylalanine hydroxylase**, necessitating two mutated gene copies for the disease to occur. - This leads to the accumulation of phenylalanine, causing neurological damage if untreated. *Glucose-6 phosphate dehydrogenase deficiency* - **Glucose-6 phosphate dehydrogenase (G6PD) deficiency** is an **X-linked recessive disorder**, meaning the gene is located on the X chromosome and typically affects males more severely. - Females can be carriers, and hemizygous males (having only one X chromosome) will express the disorder if they inherit the mutated gene.

Q: The PRSS1 gene is located on?

Chr 7q. ***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.

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

Tay-Sachs disease. ***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.

Q: 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?

X-linked inheritance. ***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

Q: In which of the following inheritance patterns is father-to-son transmission not observed?

X-linked recessive inheritance. ***X-linked recessive inheritance*** - In X-linked inheritance, females have two X chromosomes (XX) and males have one X and one Y chromosome (XY). A father always passes his **Y chromosome** to his son. - He passes his **X chromosome only to his daughters**. Therefore, a father cannot pass an X-linked trait directly to his son. *Autosomal dominant inheritance* - In autosomal dominant inheritance, a disease allele is located on a **non-sex chromosome (autosome)**. - Both males and females can be affected, and **father-to-son transmission is possible** if the father carries the dominant allele on an autosome. *Autosomal recessive inheritance* - This inheritance pattern also involves genes on **autosomes**. - A father can transmit a recessive allele to his son, though the son would only express the trait if he also inherits a recessive allele from his mother. **Father-to-son transmission of the allele is possible**. *Multifactorial inheritance* - This pattern involves the interaction of **multiple genes** and **environmental factors**. - As some of these genes are on autosomes, and environmental factors are independent of sex chromosomes, **father-to-son transmission is observed** for the genetic components.

Q: What is the type of inheritance in MELAS?

Mitochondrial. ***Mitochondrial*** - **MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes)** is caused by mutations in **mitochondrial DNA**. - **Mitochondrial inheritance** shows **maternal transmission** - the disease is passed from mothers to all of their children (both sons and daughters), but **only daughters can transmit it to the next generation** as sons do not pass on mitochondrial DNA. - This occurs because mitochondria are inherited exclusively from the egg (maternal), not from sperm. *X-linked Recessive* - **X-linked recessive disorders** primarily affect males, as they only have one X chromosome. - The disease is typically transmitted by carrier mothers to their sons, which is not characteristic of MELAS. *Autosomal Recessive* - In **autosomal recessive inheritance**, an individual must inherit two copies of the mutated gene (one from each parent) to be affected. - This pattern of inheritance does not explain the strict maternal transmission observed in MELAS. *X-linked Dominant* - **X-linked dominant disorders** can affect both males and females, but females are often more mildly affected. - All daughters of an affected father will inherit the condition, which differs from the maternal-only inheritance pattern of MELAS.

Q: In Marfan syndrome, the defect is in the gene encoding which protein?

Fibrillin I. ***Fibrillin I*** - Marfan syndrome arises from a defect in **fibrillin I**, which is essential for the proper formation of elastic fibers in connective tissue [1]. - This defect leads to symptoms affecting the **musculoskeletal**, **cardiovascular**, and **ocular systems** due to weakened connective tissue structure [1]. *Collagen* - While collagen is an important structural protein, it is not the primary defect in Marfan syndrome. - Disorders affecting collagen include **Ehlers-Danlos syndrome**, which presents with different clinical features such as hypermobility. *Fibrillin II* - Fibrillin II is related to different connective tissue conditions but is not involved in Marfan syndrome. - Its mutations are associated with **other disorders**, not the hallmark manifestations seen in Marfan. *Elastin* - Elastin provides elasticity in vascular and other tissues; however, it is not directly related to Marfan syndrome. - Conditions such as **Williams syndrome** involve elastin, but they present distinct clinical features from Marfan syndrome. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. With Illustrations By, pp. 35-36.

Q: Enzyme deficiencies are seen in genetic diseases such as?

Tay-Sachs disease. ***Tay-Sachs disease*** - Tay-Sachs disease is a **lysosomal storage disorder** caused by a deficiency of the enzyme **hexosaminidase A**. - This enzyme deficiency leads to the accumulation of **GM2 gangliosides** in neurons, resulting in progressive neurological degeneration. *Sickle Cell Anemia* - Sickle cell anemia is a **hemoglobinopathy** caused by a genetic mutation affecting the structure of the **beta-globin chain** of hemoglobin, leading to abnormal red blood cell shape. - It is not primarily due to an enzyme deficiency, but rather a structural protein defect. *Cystic Fibrosis* - Cystic fibrosis is caused by a mutation in the **CFTR gene**, which encodes a **chloride channel protein**. - This defect affects chloride transport across cell membranes, leading to thick, viscous secretions in various organs, not an enzyme deficiency. *Duchenne Muscular Dystrophy* - Duchenne muscular dystrophy is an **X-linked recessive disorder** characterized by a deficiency of the protein **dystrophin**. - Dystrophin is a structural protein essential for muscle cell integrity; its absence leads to progressive muscle degeneration, not an enzyme deficiency.

Q: Which of the following conditions is characterized by depletion of mitochondrial DNA?

Mitochondrial DNA depletion syndrome. ***Mitochondrial DNA depletion syndrome*** - This syndrome is directly characterized by a significant **reduction in the copy number of mitochondrial DNA (mtDNA)** in affected tissues, leading to impaired mitochondrial function. - The depletion results in a broad spectrum of clinical manifestations, including **neurological, hepatic, and myopathic symptoms**, depending on the specific gene mutation involved (e.g., POLG, DGUOK, TK2, SUCLA2). *Leigh syndrome* - Leigh syndrome is a severe neurological disorder characterized by **psychomotor regression and brain lesions** in specific areas (basal ganglia, brainstem). - While some cases can involve mtDNA depletion (e.g., POLG mutations), Leigh syndrome is a **clinical diagnosis** defined by its characteristic neuropathological features, not specifically by the mechanism of mitochondrial dysfunction. - Most cases result from **defects in oxidative phosphorylation enzymes** or specific mtDNA point mutations rather than quantitative mtDNA depletion. *Mitochondrial myopathy* - Mitochondrial myopathies are a heterogeneous group of disorders primarily affecting skeletal muscle, characterized by **muscle weakness, exercise intolerance**, and sometimes "ragged red fibers" on biopsy. - They can be caused by various genetic defects, including **point mutations or large deletions** in mtDNA, but are **not specifically characterized by mtDNA depletion** as the defining feature. *Mitochondrial encephalomyopathy* - Mitochondrial encephalomyopathies are broader disorders involving multiple organ systems, particularly the brain and muscle, due to mitochondrial dysfunction. - Examples include MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes), which is caused by specific **mtDNA point mutations** (commonly m.3243A>G), rather than a quantitative reduction in mtDNA copy number.

Q: Which of the following is a cause of macrocytic anemia?

Orotic aciduria. ***Lesh nyhan disease*** - Lesh Nyhan disease primarily affects uric acid metabolism and is associated with **self-mutilating behavior**, not directly leading to macrocytic anemia. - Macrocytic anemia typically involves an **imbalance in red blood cell production** due to deficiencies in vitamins or other factors, which are not features of this condition. *Transcobalamine deficiency* - This deficiency leads to impaired transport of **cobalamin (Vitamin B12)**, resulting in **macrocytic anemia** due to ineffective erythropoiesis [2]. - Patients will often present with symptoms related to **B12 deficiency**, including neurological manifestations [2]. *Abetalipoproteinemia* - It is characterized by the inability to absorb lipids, leading to deficiencies in **fat-soluble vitamins** (A, D, E, K) and subsequent **macrocytic anemia** due to vitamin deficiencies, particularly vitamin E. - Common findings include **retinitis pigmentosa** and neurological symptoms, indicative of vitamin deficiencies. *Orotic aciduria* - This condition is due to a defect in **pyrimidine synthesis**, leading to **macrocytic anemia** because of ineffective erythropoiesis from uridine deficiency [1]. - Patients usually exhibit **growth retardation** and other metabolic issues related to the inability to synthesize nucleotides effectively [1]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Red Blood Cell and Bleeding Disorders, pp. 656-657. [2] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. Common Clinical Problems From Blood And Bone Marrow Disease, pp. 593-594.

Question 1

Which one of the following diseases is classified as an autosomal dominant disorder?

Accepted Answer

Maturity onset diabetes of the young

Answer

Hemochromatosis

Answer

Phenylketonuria

Answer

Glucose-6 phosphate dehydrogenase deficiency

Question 2

The PRSS1 gene is located on?

Accepted Answer

Chr 7q

Answer

Chr 20q

Answer

Chr 17p

Answer

Chr 1p

Question 3

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

Accepted Answer

Tay-Sachs disease

Answer

Cystic fibrosis

Answer

Liddle's syndrome

Answer

Hypokalemic periodic paralysis

Question 4

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?

Accepted Answer

X-linked inheritance

Answer

Autosomal recessive

Answer

Mitochondrial inheritance

Answer

Multifactorial inheritance

Question 5

In which of the following inheritance patterns is father-to-son transmission not observed?

Accepted Answer

X-linked recessive inheritance

Answer

Autosomal dominant inheritance

Answer

Autosomal recessive inheritance

Answer

Multifactorial inheritance

Question 6

What is the type of inheritance in MELAS?

Accepted Answer

Mitochondrial

Answer

X-linked Recessive

Answer

Autosomal Recessive

Answer

X-linked Dominant

Question 7

In Marfan syndrome, the defect is in the gene encoding which protein?

Accepted Answer

Fibrillin I

Answer

Fibrillin II

Answer

Elastin

Answer

Collagen

Question 8

Enzyme deficiencies are seen in genetic diseases such as?

Accepted Answer

Tay-Sachs disease

Answer

Sickle Cell Anemia

Answer

Cystic Fibrosis

Answer

Duchenne Muscular Dystrophy

Question 9

Which of the following conditions is characterized by depletion of mitochondrial DNA?

Accepted Answer

Mitochondrial DNA depletion syndrome

Answer

Leigh syndrome

Answer

Mitochondrial myopathy

Answer

Mitochondrial encephalomyopathy

Question 10

Which of the following is a cause of macrocytic anemia?

Accepted Answer

Orotic aciduria

Answer

Phenylketonuria

Answer

Lesch-Nyhan disease

Answer

Abetalipoproteinemia

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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