Genetic Disorders and Biochemical Pathology Practice Questions

Q: A one-month-old male infant presents with feeding difficulties and a history of frequent seizures. Blood investigations reveal elevated very long chain fatty acids (VLCFA). What is the likely diagnosis?

Zellweger syndrome and Cerebrohepatorenal syndrome. **Explanation:** The correct answer is **D (Zellweger syndrome and Cerebrohepatorenal syndrome)** because they are synonymous terms for the same clinical entity. **1. Understanding the Diagnosis:** Zellweger syndrome (also known as Cerebrohepatorenal syndrome) is the most severe form of **Peroxisome Biogenesis Disorders (PBD)**. It is caused by mutations in *PEX* genes, which are essential for the normal assembly of peroxisomes. Peroxisomes are responsible for the **alpha-oxidation** of branched-chain fatty acids and the **beta-oxidation** of **Very Long Chain Fatty Acids (VLCFA)** (carbon chains >22). In the absence of functional peroxisomes, VLCFAs accumulate in the blood and tissues, particularly the brain and liver, leading to the clinical triad of neurological impairment (seizures, hypotonia), hepatic dysfunction, and renal cysts. **2. Analysis of Options:** * **Option A (Refsum disease):** This is a defect specifically in **alpha-oxidation** due to a deficiency of the enzyme *Phytanoyl-CoA hydroxylase*. While it involves peroxisomal dysfunction, it results in the accumulation of **Phytanic acid**, not VLCFAs. It typically presents later in life with retinitis pigmentosa and ataxia. * **Option B & C:** While both are technically correct, they are incomplete. Since Zellweger syndrome and Cerebrohepatorenal syndrome refer to the same condition, Option D is the most accurate choice for a competitive exam. **3. High-Yield Clinical Pearls for NEET-PG:** * **Biochemical Marker:** Elevated plasma levels of **VLCFA** (C24:0 and C26:0) is the pathognomonic finding. * **Clinical Triad:** Hypotonia ("floppy infant"), seizures, and dysmorphic facial features (high forehead, widened fontanelles). * **Radiological Sign:** Stippled epiphyses (chondrodysplasia punctata) may be seen on X-ray. * **Prognosis:** Usually fatal within the first year of life.

Q: Which chromosome is involved in Angelman syndrome?

Chromosome 15. **Explanation:** **Angelman Syndrome (AS)** is a neurodevelopmental disorder caused by the loss of function of the **UBE3A gene** located on **Chromosome 15 (15q11-q13)**. This region is subject to **genomic imprinting**, where certain genes are expressed only from one parent. In a normal individual, the maternal allele of UBE3A is active in the brain while the paternal allele is silenced. Angelman syndrome occurs when the **maternal contribution** is lost (via deletion, uniparental disomy, or imprinting defects), leading to a lack of UBE3A protein expression. **Analysis of Incorrect Options:** * **Option A (Chromosome 13):** Associated with **Patau Syndrome** (Trisomy 13) and Wilson’s disease. * **Option C (Chromosome 18):** Associated with **Edwards Syndrome** (Trisomy 18). * **Option D (Chromosome 21):** Associated with **Down Syndrome** (Trisomy 21). **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic:** **"MAMA"** – **M**aternal **A**ngelman, **M**ental retardation, **A**taxia/Antsy (hyperactivity). * **Clinical Features:** "Happy Puppet" syndrome—characterized by paroxysms of inappropriate laughter, jerky "puppet-like" movements (ataxia), microcephaly, and severe intellectual disability. * **Prader-Willi Syndrome (PWS):** This is the "sister" disorder also involving **Chromosome 15**, but it results from the loss of the **paternal** contribution (Paternal = Prader-Willi). PWS presents with hypotonia, obesity, and hyperphagia. * **Diagnostic Gold Standard:** DNA methylation analysis (detects ~80% of cases).

Q: Which of the following genetic disorders does not have an available enzyme replacement therapy?

Tay-Sachs disease. **Explanation:** The correct answer is **Tay-Sachs disease**. The primary challenge in treating Lysosomal Storage Diseases (LSDs) with Enzyme Replacement Therapy (ERT) is the **Blood-Brain Barrier (BBB)**. ERT involves the intravenous administration of recombinant enzymes, which are large polar molecules that cannot cross the BBB to reach the Central Nervous System (CNS). 1. **Why Tay-Sachs is the correct answer:** Tay-Sachs disease is caused by a deficiency of **Hexosaminidase A**, leading to the accumulation of GM2 gangliosides primarily in the neurons. Because the pathology is almost exclusively neurological, systemic ERT is ineffective as it cannot reach the brain. Currently, management is supportive, though gene therapy and substrate reduction therapy are under investigation. 2. **Why other options are incorrect:** * **Gaucher’s Disease (Type 1):** The first LSD for which ERT (**Imiglucerase**) was developed. Since Type 1 lacks CNS involvement, ERT effectively manages hepatosplenomegaly and bone crises. * **Pompe’s Disease:** Caused by Acid Alpha-glucosidase deficiency. ERT (**Alglucosidase alfa**) is available and targets cardiac and skeletal muscle. * **Hurler Syndrome (MPS I):** Treated with ERT (**Laronidase**). While ERT helps systemic symptoms, it does not fix cognitive decline, which is why Hematopoietic Stem Cell Transplant (HSCT) is often preferred for CNS benefits. **High-Yield Clinical Pearls for NEET-PG:** * **Tay-Sachs Hallmark:** Cherry-red spot on the macula + **No hepatosplenomegaly** (distinguishes it from Niemann-Pick). * **Enzyme Mnemonic:** "Tay-Sa**X** lacks He**X**osaminidase." * **ERT Limitation:** Always remember that standard IV ERT is effective for visceral symptoms but generally fails to treat the neurodegenerative components of LSDs.

Q: What is the inheritance pattern of congenital adrenal hyperplasia?

Autosomal Recessive (AR). **Explanation:** **Congenital Adrenal Hyperplasia (CAH)** is a group of inherited disorders characterized by a deficiency in one of the enzymes required for cortisol synthesis in the adrenal cortex. 1. **Why Autosomal Recessive (AR) is correct:** CAH follows an **Autosomal Recessive** inheritance pattern. This means an affected individual must inherit two mutated alleles (one from each parent). The parents are typically asymptomatic carriers. The most common cause (95% of cases) is a deficiency of the enzyme **21-hydroxylase**, encoded by the *CYP21A2* gene located on Chromosome 6. Because it is an enzymatic defect, it follows the general rule in genetics that most inborn errors of metabolism are inherited in an AR fashion. 2. **Why other options are incorrect:** * **Autosomal Dominant (AD):** AD disorders usually involve structural proteins or receptors (e.g., Marfan syndrome). CAH involves enzyme deficiencies, which rarely manifest in a heterozygous state. * **X-linked (XD/XR):** CAH affects males and females equally and involves genes located on autosomes (like Chromosome 6 or 11), ruling out sex-linked inheritance. **High-Yield Clinical Pearls for NEET-PG:** * **Most Common Enzyme Deficiency:** 21-hydroxylase deficiency (leads to increased 17-OH Progesterone). * **Classic Presentation:** Salt-wasting (hyponatremia, hyperkalemia, hypotension) and virilization (ambiguous genitalia in females). * **Diagnostic Marker:** Elevated serum **17-hydroxyprogesterone (17-OHP)**. * **Treatment:** Glucocorticoids (to suppress ACTH and replace cortisol) and Mineralocorticoids (Fludrocortisone for salt-wasters). * **Screening:** Newborn screening for CAH is now part of many national programs using the heel-prick test for 17-OHP.

Q: The gene for the disease with the following features is localized to which chromosome?

11q. ***11q*** - The **ATM gene** responsible for **Ataxia-Telangiectasia** (Louis-Bar syndrome) is located on chromosome **11q22-23**. - This autosomal recessive disorder presents with **cerebellar ataxia**, **oculocutaneous telangiectasia**, **immunodeficiency**, and **radiosensitivity**. *12p* - Chromosome 12p is associated with **von Willebrand disease** type 2N and some **lipodystrophy syndromes**. - This location does not harbor genes responsible for disorders with cerebellar ataxia and telangiectasia features. *21p* - Chromosome 21p contains genes associated with **Down syndrome** when present in trisomy. - This chromosomal region is not linked to ataxia-telangiectasia or similar neurodegenerative disorders. *18q* - Chromosome 18q deletions are associated with **18q deletion syndrome** causing developmental delays and growth retardation. - This location does not contain genes responsible for the combination of ataxia, telangiectasia, and immunodeficiency.

Q: A sick child presents with a low white blood cell count, metabolic acidosis, an increased anion gap, and mild hyperammonemia. Plasma amino acid measurements reveal elevated glycine, and urinary organic acid measurements reveal increased amounts of propionic acid and methyl citrate. Which of the following processes is most likely indicated?

Propionic acidemia. **Explanation:** The clinical presentation of metabolic acidosis with an increased anion gap, ketosis (implied by the presence of methyl citrate), and hyperammonemia in a sick child is characteristic of an **Organic Acidemia**. **1. Why Propionic Acidemia is correct:** Propionic acidemia is caused by a deficiency of **Propionyl-CoA carboxylase**, a biotin-dependent enzyme. This enzyme normally converts propionyl-CoA to methylmalonyl-CoA. When deficient, propionyl-CoA accumulates and is diverted into alternative pathways, forming **propionic acid** and **methyl citrate**. * **Hyperglycinemia:** High propionyl-CoA levels inhibit the glycine cleavage system, leading to elevated plasma glycine. * **Hyperammonemia:** Accumulation of propionyl-CoA inhibits N-acetylglutamate synthase, which is essential for the urea cycle. * **Bone Marrow Suppression:** Organic acids are toxic to the marrow, explaining the low WBC count (neutropenia). **2. Why other options are incorrect:** * **A. Glycine catabolism disorder:** While glycine is elevated (Non-ketotic hyperglycinemia), it does not present with metabolic acidosis or organic aciduria. * **C. Fatty acid oxidation disorder:** These typically present with *hypoketotic* hypoglycemia and would not show elevated propionic acid or methyl citrate. * **D. Vitamin B12 deficiency:** While B12 deficiency causes Methylmalonic Aciduria (due to methylmalonyl-CoA mutase dysfunction), the specific elevation of propionic acid and methyl citrate without mention of methylmalonic acid points directly to Propionyl-CoA carboxylase deficiency. **Clinical Pearls for NEET-PG:** * **VOMIT mnemonic:** Precursors of Propionyl-CoA are **V**aline, **O**dd-chain fatty acids, **M**ethionine, **I**soleucine, and **T**hreonine. * **Biotin (B7)** is the essential cofactor for Propionyl-CoA carboxylase. * **Methyl citrate** is a pathognomonic marker for propionic acidemia in urine organic acid analysis.

Q: Which of the following syndromes is/are associated with mitochondrial inheritance?

All of the above. **Explanation:** Mitochondrial inheritance (maternal inheritance) occurs because mitochondria are transmitted exclusively through the oocyte [1]. These disorders typically affect tissues with high energy requirements, such as the brain, heart, and skeletal muscles [1]. **Why "All of the above" is correct:** * **MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes):** This is the most common mitochondrial disorder. It is characterized by stroke-like episodes before age 40, seizures, and lactic acidosis. * **NARP (Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa):** This syndrome is caused by mutations in the *MT-ATP6* gene. It presents with sensory tremors, proximal muscle weakness, and pigmentary retinopathy [1]. * **Leigh’s Syndrome (Subacute Necrotizing Encephalomyelopathy):** This is a severe neurological disorder typically manifesting in infancy. While it can be inherited via nuclear DNA (autosomal recessive), the **mitochondrial DNA (mtDNA) mutation** (often involving the same *MT-ATP6* gene as NARP) is a classic and frequently tested cause. **High-Yield Clinical Pearls for NEET-PG:** 1. **Heteroplasmy:** The presence of a mixture of more than one type of organellar genome (mutated vs. normal mtDNA) within a cell. This explains the clinical variability in mitochondrial diseases. 2. **Maternal Inheritance:** An affected mother passes the trait to **all** her children, but an affected father passes it to **none** [1]. 3. **Ragged Red Fibers:** On muscle biopsy (Gomori trichrome stain), these are a hallmark of mitochondrial myopathies (especially MERRF). 4. **Other common examples:** MERRF (Myoclonic Epilepsy with Ragged Red Fibers) and LHON (Leber’s Hereditary Optic Neuropathy).

Q: Enzyme replacement therapy is available for all of the following conditions except:

Sanfilippo disease. **Explanation:** The correct answer is **Sanfilippo disease (Mucopolysaccharidosis III)**. The primary challenge in Enzyme Replacement Therapy (ERT) for Lysosomal Storage Disorders (LSDs) is the **Blood-Brain Barrier (BBB)**. Intravenously administered enzymes are large molecules that cannot cross the BBB to reach the Central Nervous System (CNS). * **Sanfilippo disease** is characterized predominantly by severe, progressive neurological deterioration and cognitive decline. Because the pathology is almost exclusively within the CNS, standard systemic ERT is ineffective. While research into intrathecal delivery is ongoing, there is currently no FDA-approved ERT for Sanfilippo syndrome. * **Gaucher’s disease (Type 1):** This was the first LSD treated with ERT (Imiglucerase). It targets systemic manifestations like hepatosplenomegaly and cytopenia. * **Pompe disease:** Treated with Alglucosidase alfa, which targets the accumulation of glycogen in cardiac and skeletal muscle. * **Fabry disease:** Treated with Agalsidase alfa/beta to manage systemic complications like renal failure and cardiovascular issues. **NEET-PG High-Yield Pearls:** 1. **Gaucher Disease:** Most common LSD; characterized by "crumpled tissue paper" appearance of macrophages. 2. **Pompe Disease:** The only glycogen storage disease (Type II) that is also a lysosomal storage disorder (Acid maltase deficiency). 3. **Sanfilippo Syndrome:** Caused by a deficiency in enzymes required to break down **Heparan sulfate**. 4. **I-Cell Disease:** Caused by a failure of mannose-6-phosphate tagging, leading to enzymes being secreted extracellularly rather than reaching lysosomes.

Q: A 6-year-old mentally retarded male patient presents with hepatosplenomegaly, coarse facial features, corneal clouding, a large tongue, prominent forehead, joint stiffness, short stature, and skeletal dysplasia. What is the diagnosis?

Hurler’s Disease. ### Explanation The clinical presentation describes a classic case of **Hurler’s Disease (MPS IH)**, the most severe form of Mucopolysaccharidosis. It is caused by a deficiency of the lysosomal enzyme **$\alpha$-L-iduronidase**, leading to the accumulation of dermatan sulfate and heparan sulfate. **Why Hurler’s Disease is Correct:** The presence of **corneal clouding** combined with mental retardation, hepatosplenomegaly, and skeletal deformities (dysostosis multiplex) is the pathognomonic triad for Hurler’s. The "coarse" facial features (gargoylism) and macroglossia are due to the progressive deposition of glycosaminoglycans (GAGs) in various tissues. **Analysis of Incorrect Options:** * **Hunter Disease (MPS II):** Clinically similar to Hurler’s but distinguished by the **absence of corneal clouding** and an **X-linked recessive** inheritance (Hurler is Autosomal Recessive). Patients often exhibit aggressive behavior. * **Natowicz Syndrome (MPS IX):** A very rare deficiency of hyaluronidase. It typically presents with periarticular soft tissue masses and short stature, but lacks the severe systemic and corneal involvement seen here. * **Maroteaux-Lamy Syndrome (MPS VI):** While it features corneal clouding and skeletal dysplasia, **intellectual ability is typically normal**. The mental retardation in this case points specifically toward Hurler’s. **High-Yield NEET-PG Pearls:** * **Enzyme Defect:** $\alpha$-L-iduronidase (Hurler) vs. Iduronate sulfatase (Hunter). * **Inheritance:** All MPS are Autosomal Recessive except Hunter (X-linked). * **Urine Test:** Positive for increased GAGs (Dermatan and Heparan sulfate). * **Zebra Bodies:** Characteristic inclusion bodies seen on electron microscopy in MPS. * **Memory Aid:** "The **Hunter** needs clear eyes to see the **X** (X-linked) on the target" (No corneal clouding in Hunter).

Question 1

Mitochondrial DNA linked disease is characterized by which mode of inheritance?

Accepted Answer

Transmitted by females

Answer

More common in males

Answer

Variable penetrance in families

Answer

Autosomal inheritance

Question 2

A one-month-old male infant presents with feeding difficulties and a history of frequent seizures. Blood investigations reveal elevated very long chain fatty acids (VLCFA). What is the likely diagnosis?

Accepted Answer

Zellweger syndrome and Cerebrohepatorenal syndrome

Answer

Refsum disease

Answer

Zellweger syndrome

Answer

Cerebrohepatorenal syndrome

Question 3

Which chromosome is involved in Angelman syndrome?

Accepted Answer

Chromosome 15

Answer

Chromosome 13

Answer

Chromosome 18

Answer

Chromosome 21

Question 4

Which of the following genetic disorders does not have an available enzyme replacement therapy?

Accepted Answer

Tay-Sachs disease

Answer

Gaucher's disease

Answer

Pompe's disease

Answer

Hurler syndrome

Question 5

What is the inheritance pattern of congenital adrenal hyperplasia?

Accepted Answer

Autosomal Recessive (AR)

Answer

Autosomal Dominant (AD)

Answer

X-linked Dominant (XD)

Answer

X-linked Recessive (XR)

Question 6

The gene for the disease with the following features is localized to which chromosome?

Accepted Answer

11q

Answer

12p

Answer

21p

Answer

18q

Question 7

A sick child presents with a low white blood cell count, metabolic acidosis, an increased anion gap, and mild hyperammonemia. Plasma amino acid measurements reveal elevated glycine, and urinary organic acid measurements reveal increased amounts of propionic acid and methyl citrate. Which of the following processes is most likely indicated?

Accepted Answer

Propionic acidemia

Answer

Glycine catabolism disorder

Answer

Fatty acid oxidation disorder

Answer

Vitamin B12 deficiency

Question 8

Which of the following syndromes is/are associated with mitochondrial inheritance?

Accepted Answer

All of the above

Answer

Leigh's syndrome

Answer

NARP syndrome

Answer

MELAS syndrome

Question 9

Enzyme replacement therapy is available for all of the following conditions except:

Accepted Answer

Sanfilippo disease

Answer

Gaucher's disease

Answer

Pompe disease

Answer

Fabry disease

Question 10

A 6-year-old mentally retarded male patient presents with hepatosplenomegaly, coarse facial features, corneal clouding, a large tongue, prominent forehead, joint stiffness, short stature, and skeletal dysplasia. What is the diagnosis?

Accepted Answer

Hurler’s Disease

Answer

Hunter Disease

Answer

Natowicz syndrome

Answer

Maroteaux-Lamy syndrome

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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