Genetic Disorders and Biochemical Pathology Practice Questions

Q: Duchenne's muscular dystrophy follows which inheritance pattern?

X-Linked recessive. ***X-Linked recessive*** - **Duchenne's muscular dystrophy (DMD)** is a classic example of an **X-linked recessive** genetic disorder, primarily affecting males. - The gene responsible for producing **dystrophin** is located on the X chromosome; males have only one X chromosome, so a single defective copy leads to the disease. *X-Linked dominant* - In **X-linked dominant** disorders, only one copy of the affected gene on the X chromosome is sufficient to cause the disorder, affecting both males and females, but often with more severe manifestations in males. - Examples include **Fragile X syndrome** and **Rett syndrome**, which do not fit the clinical presentation of DMD. *Autosomal dominant* - **Autosomal dominant** disorders are caused by a mutation in a single copy of a gene on one of the **non-sex chromosomes** (autosomes). - This inheritance pattern means that an affected individual has a 50% chance of passing the disorder to each child, regardless of sex, which is not characteristic of DMD. *Autosomal recessive* - **Autosomal recessive** disorders require an individual to inherit two copies of the mutated gene (one from each parent) to develop the condition. - While other muscular dystrophies like **limb-girdle muscular dystrophy** can be autosomal recessive, DMD specifically follows an X-linked recessive pattern.

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 gene is mutated in Waardenburg syndrome?

PAX3 gene. ***PAX3 gene*** - Mutations in the **PAX3 gene** are the most common cause of **Waardenburg syndrome type 1 (WS1)** and **type 3 (WS3)**. - The PAX3 gene is crucial for the development of **melanocytes** and structures derived from the **neural crest**, explaining the characteristic pigmentary abnormalities and craniofacial features of the syndrome. *PAX2 gene* - Mutations in the **PAX2 gene** are primarily associated with conditions affecting **kidney and ear development**, such as **renal-coloboma syndrome**. - It plays a critical role in **renal and optic nerve development**, which are generally not the primary features of Waardenburg syndrome. *PAX6 gene* - The **PAX6 gene** is a master control gene for **eye development** and is associated with conditions like **aniridia** (absence of the iris). - Its mutations typically lead to severe ocular malformations, which are distinct from the general presentation of Waardenburg syndrome. *PAX9 gene* - **PAX9 gene** mutations are linked to **tooth agenesis** or **oligodontia**, affecting the development and eruption of teeth. - This gene is particularly involved in **odontogenesis** and craniofacial development, but not typically in the pigmentary or hearing defects seen in Waardenburg syndrome.

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.

Q: Deficiency of which of the following micronutrients results in Menkes syndrome?

Copper. **Copper** - **Menkes syndrome** is a genetic disorder caused by a defect in the **ATP7A gene**, leading to impaired cellular copper transport and severe **copper deficiency**. - This deficiency affects multiple organ systems, resulting in characteristic features like **kinky hair**, **neurological degeneration**, and connective tissue abnormalities. *Magnesium* - Magnesium deficiency is associated with conditions like **hypomagnesemia**, muscle weakness, and cardiac arrhythmias. - It plays crucial roles in enzyme function and nerve conduction but is not directly linked to Menkes syndrome. *Selenium* - Selenium deficiency can cause **Keshan disease** (cardiomyopathy) and **myxedematous endemic cretinism**. - While an essential trace element, its deficiency does not lead to Menkes syndrome. *Manganese* - Manganese is a cofactor for several enzymes involved in metabolism and antioxidant defense. - Deficiency is rare and typically presents with impaired growth and bone development, which are distinct from Menkes syndrome.

Q: Which of the following statements about the genetic basis of Fragile X syndrome is true?

It is caused by a CGG repeat expansion in the FMR1 gene.. ***Triple nucleotide repeat sequence*** - Fragile-X syndrome is caused by the **expansion of a CGG repeat** in the FMR1 gene on the X chromosome [1]. - This genetic alteration leads to **loss of function** of the FMRP protein, resulting in developmental delays and intellectual disabilities [1]. *Centrachrome absent* - Centrachrome is not a relevant term or feature associated with fragile-X syndrome. - The syndrome is characterized by specific **genetic mutations**, not the absence of centrachrome. *Chromosome breaking* - While fragile-X syndrome affects the X chromosome, it does **not involve breaking** of chromosomes in the conventional sense. - Instead, it is marked by **instability of the CGG repeats** [1], rather than actual chromosome fragmentation. *Mitochondrial mutation* - Fragile-X syndrome is not related to **mitochondrial DNA**, as it is a result of a mutation in the nuclear DNA. - Symptoms and inheritance patterns differ significantly from those of **mitochondrial disorders**. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 177-181.

Q: What is the karyotype of a patient with androgen insensitivity syndrome?

46,XY. ***46,XY*** - Patients with **androgen insensitivity syndrome (AIS)** are genetically male with a **46,XY karyotype**, meaning they have a Y chromosome and thus an SRY gene. - The syndrome arises from a **defect in androgen receptors**, leading to an inability of target tissues to respond to testosterone and other androgens, despite their presence. - In complete AIS, individuals have a **female external phenotype** despite being genetically male. *46,XX* - This karyotype represents a **genetically female individual** who would typically develop female secondary sexual characteristics. - Individuals with AIS are genetically male and, despite outwardly female characteristics in complete AIS, possess a Y chromosome. *47,XXY* - This karyotype describes **Klinefelter syndrome**, a condition where males have an extra X chromosome. - Individuals with Klinefelter syndrome typically present with hypogonadism, infertility, and often tall stature, which is distinct from AIS where the primary issue is androgen receptor function. *48,XXYY* - This karyotype represents a **sex chromosome aneuploidy** with two extra sex chromosomes. - Affected individuals are phenotypically male with features that may include tall stature, developmental delays, and hypogonadism. - It is not associated with androgen insensitivity syndrome, which specifically involves normal androgen production but impaired receptor function in 46,XY individuals.

Q: Prader-Willi syndrome and Angelman syndrome are examples of what genetic phenomenon?

Genomic Imprinting. ***Genomic Imprinting*** - **Genomic imprinting** is an epigenetic phenomenon where certain genes are expressed in a **parent-of-origin-specific manner**. - In Prader-Willi syndrome, the disease results from the loss of function of specific genes on chromosome 15 (15q11-q13) inherited from the father, while Angelman syndrome results from the loss of function of a different gene (UBE3A) in the same region, but inherited from the mother. *RNA interference* - **RNA interference** is a biological process in which RNA molecules inhibit gene expression or translation, by neutralizing targeted mRNA molecules. - This process is not directly responsible for the parent-of-origin-specific expression patterns observed in these syndromes. *Gene Knockout* - A **gene knockout** is a genetic technique in which an organism's genes are made inoperative. - While it involves modifying gene function, it does not explain the differential expression based on parental origin. *Impaired DNA repair* - **Impaired DNA repair** refers to defects in the mechanisms that correct DNA damage. - This can lead to increased mutations and conditions like cancer, but it is not the underlying mechanism for Prader-Willi or Angelman syndromes.

Q: What term describes a chromosomal number that is an exact multiple of 23?

Euploidy. ***Euploidy*** - Euploidy refers to the condition where the **chromosomal number is an exact multiple of 23**, indicating a complete set of chromosomes. - This condition represents the normal state for organisms and includes multiples like **diploidy (2n)** and **triploidy (3n)**. *Aneuploidy* - Aneuploidy is an **abnormal chromosomal number** that is not a complete multiple of 23, leading to conditions like **trisomy** or **monosomy** [1]. - It typically results in **genetic disorders** such as Down syndrome (Trisomy 21) due to the presence of an extra chromosome [1]. *Trisomy* - Trisomy specifically refers to the presence of an **extra chromosome** in a pair, resulting in a total of 47 chromosomes instead of the normal 46 [1]. - It is a specific type of **aneuploidy**, making it not a complete multiple of 23 in the context discussed [1]. *Mosaicism* - Mosaicism describes a situation where an individual has **two or more genetically different cell lines**, leading to a mix of normal and abnormal cells [1]. - It does not inherently correspond to an **exact multiple** of chromosome sets, thus not applicable here [1]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 168-169.

Q: Orotic aciduria is due to deficiency of:

UMP synthase. ***UMP synthase*** - **Orotic aciduria** results from a deficiency in **UMP synthase**, a bifunctional enzyme with **orotate phosphoribosyltransferase** and **OMP decarboxylase** activities. - This deficiency leads to an accumulation of **orotic acid** due to the inability to convert **orotate** to **uridine monophosphate (UMP)**, affecting pyrimidine synthesis. *Ornithine transcarbamylase* - Deficiency in **ornithine transcarbamylase (OTC)** causes **hyperammonemia** and increased plasma **glutamine**, as it's involved in the urea cycle. - While it causes elevated **orotic acid**, this accumulation is due to excess **carbamoyl phosphate** shunting to pyrimidine synthesis, not a direct pyrimidine synthesis defect. *Argininosuccinate lyase* - A deficiency in **argininosuccinate lyase** leads to **argininosuccinic aciduria**, characterized by the accumulation of **argininosuccinic acid** and **hyperammonemia**. - This enzyme is also part of the **urea cycle**, and its dysfunction does not directly cause **orotic aciduria** as its primary symptom. *Carbamoyl phosphate synthetase I* - Deficiency of **carbamoyl phosphate synthetase I (CPS1)** results in severe **hyperammonemia** immediately after birth, as it's the first enzyme in the **urea cycle**. - Unlike **OTC deficiency**, CPS1 deficiency typically does not lead to **elevated orotic acid**, because the upstream precursor **carbamoyl phosphate** is not overproduced and shunted to pyrimidine synthesis.

Question 1

Duchenne's muscular dystrophy follows which inheritance pattern?

Accepted Answer

X-Linked recessive

Answer

X-Linked dominant

Answer

Autosomal dominant

Answer

Autosomal recessive

Question 2

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 3

Which gene is mutated in Waardenburg syndrome?

Accepted Answer

PAX3 gene

Answer

PAX2 gene

Answer

PAX6 gene

Answer

PAX9 gene

Question 4

Which of the following is a cause of macrocytic anemia?

Accepted Answer

Orotic aciduria

Answer

Phenylketonuria

Answer

Lesch-Nyhan disease

Answer

Abetalipoproteinemia

Question 5

Deficiency of which of the following micronutrients results in Menkes syndrome?

Accepted Answer

Copper

Answer

Magnesium

Answer

Selenium

Answer

Manganese

Question 6

Which of the following statements about the genetic basis of Fragile X syndrome is true?

Accepted Answer

It is caused by a CGG repeat expansion in the FMR1 gene.

Answer

It is caused by a mutation in mitochondrial DNA.

Answer

It is associated with chromosomal instability.

Answer

It is caused by centromere abnormalities.

Question 7

What is the karyotype of a patient with androgen insensitivity syndrome?

Accepted Answer

46,XY

Answer

47,XXY

Answer

48,XXYY

Answer

46,XX

Question 8

Prader-Willi syndrome and Angelman syndrome are examples of what genetic phenomenon?

Accepted Answer

Genomic Imprinting

Answer

Gene Knockout

Answer

Impaired DNA repair

Answer

RNA interference

Question 9

What term describes a chromosomal number that is an exact multiple of 23?

Accepted Answer

Euploidy

Answer

Aneuploidy

Answer

Mosaicism

Answer

Trisomy

Question 10

Orotic aciduria is due to deficiency of:

Accepted Answer

UMP synthase

Answer

Ornithine transcarbamylase

Answer

Argininosuccinate lyase

Answer

Carbamoyl phosphate synthetase I

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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