Genetics and Disease Practice Questions

Q: A 25-year-old with Gaucher disease type 1 and a GBA mutation, exhibiting significant residual β-glucocerebrosidase activity, what is the best initial treatment?

SRT with eliglustat. **SRT with eliglustat** - *Eliglustat* is a **substrate reduction therapy (SRT)** that inhibits glucosylceramide synthase, reducing the production of glucocerebroside. - It is particularly effective for patients with **Gaucher disease type 1 (GD1)** who have certain *GBA mutations* and **residual β-glucocerebrosidase activity**, as indicated in the patient scenario. *ERT with imiglucerase* - **Enzyme replacement therapy (ERT)** using *imiglucerase* replaces the deficient enzyme, β-glucocerebrosidase. - While effective for GD1, *SRT* is often preferred as a first-line oral treatment for patients with an eligible genotype and **residual enzyme activity**, avoiding intravenous infusions. *Chaperone tx with miglustat* - *Miglustat* is another *SRT*, but it is typically used for patients with **Gaucher disease type 1** who cannot receive *ERT* or as an adjunct. - It has a less favorable side effect profile, including *gastrointestinal disturbances* and *peripheral neuropathy*, compared to *eliglustat*. *BMT* - **Bone marrow transplantation (BMT)** is a curative, but highly invasive and risky, treatment option for Gaucher disease. - It is generally reserved for severe cases, especially those with **neuropathic forms (type 2 or 3)**, or in patients unresponsive to other therapies, given its significant *morbidity and mortality risks*.

Q: Which of the following is NOT a feature of Abetalipoproteinemia?

Elevated plasma apolipoprotein B levels. Elevated plasma apolipoprotein B levels - **Abetalipoproteinemia** is characterized by the **absence** or extremely **low levels** of apolipoprotein B due to a defect in microsomal triglyceride transfer protein (MTP). - This genetic disorder prevents the assembly and secretion of **chylomicrons**, **VLDL**, and **LDL**, all of which contain apolipoprotein B. *Plasma levels of cholesterol and triglyceride are extremely low* - This is a direct consequence of the inability to form and secrete lipoproteins such as **chylomicrons** (transport dietary triglycerides) and **VLDL/LDL** (transport endogenous lipids and cholesterol). - The lack of these lipoproteins results in **malabsorption of fats** and fat-soluble vitamins, contributing to the low plasma lipid levels. *Manifest in early childhood with diarrhea* - **Fat malabsorption** due to the absence of chylomicrons leads to **steatorrhea** (fatty stools), which is often observed as chronic diarrhea in infancy. - Failure to thrive and abdominal distension are also common early GI symptoms. *Progressive pigmented retinopathy seen* - This is a neurological and ocular manifestation resulting from severe **deficiency of fat-soluble vitamins**, particularly **vitamin A and E** [1]. - **Vitamin A deficiency** contributes to poor vision and **retinopathy**, while **vitamin E deficiency** leads to progressive neurological symptoms like ataxia and peripheral neuropathy [1].

Q: Following genetic counselling in a family for Familial polyposis coli (FPC), what is the next appropriate screening test for at-risk individuals?

Colonoscopy. Colonoscopy - **Colonoscopy** is the gold standard for screening individuals at risk for **Familial Adenomatous Polyposis (FAP)**, also known as Familial Polyposis Coli (FPC), as it allows for visualization of the entire colon and removal of polyps [1]. - Screening typically begins in **early adolescence (10-12 years)** due to the high risk of developing multiple adenomatous polyps and subsequent colorectal cancer [1]. Flexible sigmoidoscopy - While useful for inspecting the lower colon, a **flexible sigmoidoscopy** does not visualize the entire colon, which is essential for FAP given that polyps can occur throughout the large bowel [3]. - It would miss polyps in the **proximal colon**, leading to an inadequate assessment of cancer risk in FAP patients [1]. Occult blood in stools - Testing for **occult blood in stools** is a general screening tool for colorectal cancer but is not sensitive enough for FAP, where the goal is to detect and remove polyps before they become malignant. - A negative result does not rule out the presence of **adenomatous polyps**, which are the hallmark of FAP. APC gene - **APC gene** testing is used for **genetic diagnosis** to identify individuals who carry the FAP mutation, but it is not a screening test for adenomatous polyps or cancer themselves [2]. - Once a family member is identified with the APC gene mutation, subsequent surveillance for polyps requires direct visualization methods like colonoscopy [1].

Q: A 25-year-old man presents for a routine physical examination. He is tall and has an early diastolic murmur on examination. Based on the clinical findings, which of the following is the most likely mode of inheritance for the condition?

AD. ### AD - The combination of **tall stature** and an **early diastolic murmur** is highly suggestive of **Marfan syndrome**, which is inherited in an **autosomal dominant** pattern [1]. - This mode of inheritance means that only one copy of the mutated gene (FBN1) is sufficient to cause the disorder [1]. ### AR - **Autosomal recessive** disorders typically require two copies of a mutated gene for the condition to manifest, and patients are often born to unaffected carriers. - Marfan syndrome does not follow this inheritance pattern [1]. ### XLR - **X-linked recessive** disorders primarily affect males, with females usually being carriers or less severely affected. - While Marfan syndrome can affect both sexes, its inheritance pattern is not linked to the X chromosome. ### XLD - **X-linked dominant** disorders are passed from fathers to all daughters but not to sons, and from mothers to half of their children regardless of sex. - This pattern is not consistent with the genetic transmission of Marfan syndrome.

Q: Which karyotype is commonly associated with true hermaphroditism?

46,XX. ***46,XX*** - While various karyotypes can be associated with **true hermaphroditism**, the majority of cases (approximately 60-70%) present with a **46,XX karyotype** [1]. - This karyotype indicates the presence of **XX chromosomes**, typically associated with females, but in true hermaphroditism, both ovarian and testicular tissue are present [1]. *45,X (Turner syndrome)* - This karyotype is classically associated with **Turner syndrome**, characterized by the absence of one X chromosome [2]. - Individuals with Turner syndrome are typically phenotypically female but experience **gonadal dysgenesis**, leading to streak gonads and infertility, not the presence of both ovarian and testicular tissue [2]. *47,XY,+9* - This karyotype indicates an extra copy of chromosome 9 in an individual who is otherwise karyotypically male (XY). - This is a rare chromosomal abnormality that can lead to a variety of developmental issues and birth defects, but it is **not typically associated with true hermaphroditism**. *47,XXX* - This karyotype is known as **Triple X syndrome** or **Trisomy X**, where an individual has three X chromosomes [3]. - Individuals with Triple X syndrome are phenotypically female and often have mild or no clinical symptoms, though some may experience learning difficulties or fertility issues; it does **not involve the development of both ovarian and testicular tissue** [3].

Q: Which one of the following is an autosomal recessive disorder?

Cystic fibrosis. ***Cystic fibrosis*** - **Cystic fibrosis** is caused by mutations in the **CFTR gene**, leading to defective **chloride channel** function. - It is an **autosomal recessive disorder**, meaning an individual must inherit two copies of the mutated gene (one from each parent) to be affected. *Huntington's disease* - **Huntington's disease** is an **autosomal dominant disorder** caused by a mutation in the HTT gene. - Only one copy of the mutated gene is sufficient to cause the disease, resulting in progressive neurodegeneration. *Marfan syndrome* - **Marfan syndrome** is an **autosomal dominant disorder** affecting connective tissue, caused by mutations in the FBN1 gene. - It results in skeletal, ocular, and cardiovascular abnormalities due to defective **fibrillin-1**. *Neurofibromatosis type 1* - **Neurofibromatosis type 1** is an **autosomal dominant disorder** caused by mutations in the NF1 gene. - It is characterized by multiple neurofibromas, café-au-lait macules, and Lisch nodules.

Q: All are seen in Klinefelter syndrome, except which of the following?

Normal male phenotype. ***Normal male phenotype*** - Klinefelter syndrome (47, XXY) is characterized by a distinct phenotype that deviates from a normal male, including features such as **tall stature**, **gynecomastia**, and **small testes** [1]. - A normal male phenotype would imply the absence of these characteristic features. *Cognitive impairment* - While not severe, **mild cognitive and learning difficulties**, especially in language skills, are common in individuals with Klinefelter syndrome [1]. - This can manifest as problems with **expressive language** and **reading**. *Azoospermia* - **Azoospermia**, or the complete absence of sperm in semen, is a very common finding in Klinefelter syndrome due to testicular dysfunction and hypogonadism [1]. - This leads to **infertility**, which is a primary concern for affected individuals. *Elevated FSH level* - The **elevated FSH (follicle-stimulating hormone) level** is a hallmark of primary testicular failure in Klinefelter syndrome [1], [2]. - The damaged seminiferous tubules in the testes fail to produce inhibin, leading to a lack of negative feedback on the pituitary, thus increasing FSH [2].

Q: Revised Ghent criteria are used for the diagnosis of?

Marfan syndrome. Marfan syndrome - The Revised Ghent criteria are specifically designed for the clinical diagnosis of Marfan syndrome, evaluating major and minor criteria related to ocular, cardiovascular, skeletal, and dural manifestations. - These criteria provide a scoring system to assess the likelihood of the syndrome based on specific physical findings and genetic testing. Ehlers-Danlos syndrome - Ehlers-Danlos syndrome is diagnosed using its own specific clinical criteria, often focusing on skin hyperextensibility, joint hypermobility, and tissue fragility [1]. - There are multiple types of Ehlers-Danlos syndrome, each with distinct diagnostic features, but none rely on the Revised Ghent criteria [1]. Osteogenesis imperfecta - Osteogenesis imperfecta is primarily characterized by bone fragility and recurrent fractures, often with associated features like blue sclerae and hearing loss. - Its diagnosis is typically based on clinical presentation and confirmed by genetic testing for mutations in COL1A1 or COL1A2 genes, not the Ghent criteria. Duchenne muscular dystrophy - Duchenne muscular dystrophy is a X-linked recessive neuromuscular disorder characterized by progressive muscle weakness. - Diagnosis relies on clinical features like Gowers' sign, elevated creatine kinase (CK) levels, muscle biopsy findings, and genetic testing for mutations in the dystrophin gene.

Q: A patient diagnosed with an isolated increase in LDL, with a family history of the same disease in his father and brother, is likely to have a diagnosis of

LDL receptor mutation. ***LDL receptor mutation*** - An **isolated increase in LDL** with a strong **family history** (father and brother affected) is highly suggestive of **familial hypercholesterolemia**, which is most commonly caused by mutations in the **LDL receptor gene** [1]. - **LDL receptor mutations** lead to a reduced clearance of LDL from the blood, resulting in elevated LDL levels from birth [1]. *Familial type III hyperlipoproteinemia* - This condition is characterized by elevated levels of both **cholesterol and triglycerides**, specifically involving **remnant lipoproteins** (IDL), not an isolated increase in LDL [2]. - It is often associated with **palmar xanthomas** and **tuberous xanthomas**, which are not mentioned in the patient's presentation. *Abetalipoproteinemia* - This is a rare genetic disorder characterized by the **absence of apolipoprotein B**, leading to very low or undetectable levels of **LDL, VLDL, and chylomicrons**. - Patients typically present with **fat malabsorption, neurologic deficits**, and **retinitis pigmentosa**, which is contrary to an isolated increase in LDL. *Familial lipoprotein lipase deficiency* - This condition primarily causes a marked elevation in **chylomicrons and triglycerides** due to impaired clearance of triglyceride-rich lipoproteins. - It does not present as an isolated increase in LDL and is often associated with **eruptive xanthomas**, **pancreatitis**, and **hepatosplenomegaly**.

Q: What is the name of the treatment for type I tyrosinemia?

Nitisinone. ***Nitisinone*** - **Nitisinone** (NTBC) is the primary treatment for **tyrosinemia type I**, an inherited metabolic disorder. - It works by inhibiting **4-hydroxyphenylpyruvate dioxygenase**, an enzyme upstream in the tyrosine degradation pathway, preventing the formation of toxic metabolites. *No treatment* - Leaving **tyrosinemia type I** untreated leads to severe complications such as **liver failure**, **renal tubular dysfunction**, and **neurological crises**. - Without intervention, the disease is often **fatal** in infancy or early childhood. *Symptomatic treatment only* - While supportive care is important, **symptomatic treatment alone** is insufficient to prevent the progressive and severe organ damage associated with tyrosinemia type I. - The underlying metabolic defect producing toxic metabolites must be addressed directly to achieve positive outcomes. *Vitamin B complex* - **Vitamin B complex** is not an effective treatment for type I tyrosinemia. - While certain inborn errors of metabolism respond to specific vitamin cofactors, **tyrosinemia type I** requires specific inhibition of a metabolic pathway, which vitamins cannot provide.

Question 1

A 25-year-old with Gaucher disease type 1 and a GBA mutation, exhibiting significant residual β-glucocerebrosidase activity, what is the best initial treatment?

Accepted Answer

SRT with eliglustat

Answer

BMT

Answer

Chaperone tx with miglustat

Answer

ERT with imiglucerase

Question 2

Which of the following is NOT a feature of Abetalipoproteinemia?

Accepted Answer

Elevated plasma apolipoprotein B levels

Answer

Plasma levels of cholesterol and triglyceride are extremely low

Answer

Manifest in early childhood with diarrhea

Answer

Progressive pigmented retinopathy seen

Question 3

Following genetic counselling in a family for Familial polyposis coli (FPC), what is the next appropriate screening test for at-risk individuals?

Accepted Answer

Colonoscopy

Answer

Flexible sigmoidoscopy

Answer

Occult blood in stools

Answer

APC gene

Question 4

A 25-year-old man presents for a routine physical examination. He is tall and has an early diastolic murmur on examination. Based on the clinical findings, which of the following is the most likely mode of inheritance for the condition?

Accepted Answer

AD

Answer

AR

Answer

XLR

Answer

XLD

Question 5

Which karyotype is commonly associated with true hermaphroditism?

Accepted Answer

46,XX

Answer

47,XY,+9

Answer

45,X (Turner syndrome)

Answer

47,XXX

Question 6

Which one of the following is an autosomal recessive disorder?

Accepted Answer

Cystic fibrosis

Answer

Huntington's disease

Answer

Marfan syndrome

Answer

Neurofibromatosis type 1

Question 7

All are seen in Klinefelter syndrome, except which of the following?

Accepted Answer

Normal male phenotype

Answer

Azoospermia

Answer

Cognitive impairment

Answer

Elevated FSH level

Question 8

Revised Ghent criteria are used for the diagnosis of?

Accepted Answer

Marfan syndrome

Answer

Osteogenesis imperfecta

Answer

Duchenne muscular dystrophy

Answer

Ehlers-Danlos syndrome

Question 9

A patient diagnosed with an isolated increase in LDL, with a family history of the same disease in his father and brother, is likely to have a diagnosis of

Accepted Answer

LDL receptor mutation

Answer

Abetalipoproteinemia

Answer

Familial type III hyperlipoproteinemia

Answer

Familial lipoprotein lipase deficiency

Question 10

What is the name of the treatment for type I tyrosinemia?

Accepted Answer

Nitisinone

Answer

No treatment

Answer

Vitamin B complex

Answer

Symptomatic treatment only

Genetics and Disease — MCQs

Genetics and Disease — MCQs

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