Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology Indian Medical PG Practice Questions and MCQs

Question 601: A 6-day-old newborn infant develops lactosuria, seizures, and hypoglycemia. What is the likely diagnosis?

A. Aromatic amino aciduria (Correct Answer)
B. Phenylketonuria
C. Intrauterine infection
D. Tyrosinemia

Explanation: **Explanation:** The clinical presentation of a 6-day-old infant with **seizures, hypoglycemia, and lactosuria** is highly characteristic of **Tyrosinemia Type I** (Hereditary Tyrosinemia). In the context of this specific question, Tyrosinemia is classified under the broader category of **Aromatic Amino Aciduria** (Option A), as tyrosine is an aromatic amino acid. **Why Aromatic Amino Aciduria (Tyrosinemia) is correct:** Tyrosinemia Type I is caused by a deficiency of **fumarylacetoacetate hydrolase (FAH)**. The accumulation of toxic metabolites (like succinylacetone) leads to severe liver dysfunction and renal tubular damage (Fanconi-like syndrome). * **Lactosuria/Glycosuria:** Renal tubular dysfunction leads to the excretion of sugars and amino acids in the urine. * **Hypoglycemia:** Resulting from acute liver failure and impaired gluconeogenesis. * **Seizures:** Often secondary to hypoglycemia or hyperammonemia from liver failure. **Why other options are incorrect:** * **Phenylketonuria (PKU):** While PKU is an aromatic amino acid disorder, it typically presents later with developmental delay and "mousy" odor; it does not cause acute neonatal liver failure, hypoglycemia, or lactosuria. * **Intrauterine infection (TORCH):** May cause jaundice and seizures, but would not specifically explain the biochemical finding of lactosuria or the specific metabolic profile of tyrosinemia. * **Tyrosinemia (Option D):** While Tyrosinemia is the specific diagnosis, in many standardized formats, the broader classification (Aromatic Amino Aciduria) is used to test the student's knowledge of amino acid categories. **NEET-PG High-Yield Pearls:** * **Diagnostic Marker:** Elevated **Succinylacetone** in blood/urine is pathognomonic for Tyrosinemia Type I. * **Management:** Dietary restriction of Phenylalanine and Tyrosine + **Nitisinone (NTBC)**, which inhibits the pathway upstream to prevent toxic metabolite buildup. * **Long-term risk:** High risk of **Hepatocellular Carcinoma (HCC)** even in early childhood.

Question 602: Mutation in which of the following genes is found in Marfan's syndrome?

A. Collagen I
B. Collagen IV
C. Fibrillin I (Correct Answer)
D. Fibrillin II

Explanation: ### Explanation **Correct Answer: C. Fibrillin I** **Biochemical Basis:** Marfan syndrome is an **autosomal dominant** connective tissue disorder caused by a mutation in the **FBN1 gene** located on **chromosome 15q21**. This gene encodes **Fibrillin-1**, a large glycoprotein that serves as a major structural component of extracellular microfibrils. These microfibrils act as a scaffold for the deposition of elastin. Beyond structural integrity, Fibrillin-1 normally sequesters **Transforming Growth Factor-beta (TGF-β)**; its deficiency leads to excess TGF-β signaling, which causes deleterious effects on vascular smooth muscle and extracellular matrix degradation. **Analysis of Incorrect Options:** * **A. Collagen I:** Mutations here lead to **Osteogenesis Imperfecta**, characterized by brittle bones, blue sclera, and hearing loss. * **B. Collagen IV:** This is the primary collagen of basement membranes. Mutations result in **Alport Syndrome** (hereditary nephritis and sensorineural deafness). * **D. Fibrillin II:** Mutations in the *FBN2* gene (chromosome 5) cause **Congenital Contractural Arachnodactyly (Beals Syndrome)**. While it shares skeletal features with Marfan syndrome (long limbs), it does not typically involve the aorta or eyes. **NEET-PG High-Yield Pearls:** * **Clinical Triad:** Skeletal (arachnodactyly, pectus excavatum), Ocular (**Ectopia lentis**—classically **upward/superolateral** subluxation), and Cardiovascular. * **Most Common Cause of Death:** Aortic root dilation leading to **Aortic Dissection** or rupture. * **Microscopic Finding:** **Cystic Medial Necrosis** of the aorta (fragmentation of elastic fibers). * **Differentiation:** Unlike Homocystinuria (which has downward lens dislocation and intellectual disability), Marfan patients have normal intelligence and upward lens dislocation.

Question 603: Classic Galactosemia is due to deficiency of which enzyme?

A. Hexosaminidase
B. Glucocerebroside
C. Sphingomyelinase
D. Galactose-1-Phosphate-Uridyl-Transferase (Correct Answer)

Explanation: **Explanation:** **Classic Galactosemia** (Type 1) is an autosomal recessive disorder caused by a deficiency of the enzyme **Galactose-1-Phosphate Uridyl Transferase (GALT)**. In the normal metabolic pathway (Leloir pathway), GALT is responsible for converting Galactose-1-phosphate and UDP-glucose into UDP-galactose and Glucose-1-phosphate. Its deficiency leads to the toxic accumulation of Galactose-1-phosphate and galactitol in tissues like the liver, brain, and lens of the eye. **Analysis of Incorrect Options:** * **Hexosaminidase A:** Deficiency leads to **Tay-Sachs Disease**, a lysosomal storage disorder characterized by GM2 ganglioside accumulation and a "cherry-red spot" on the macula. * **Glucocerebrosidase:** Deficiency causes **Gaucher Disease**, the most common lysosomal storage disease, characterized by hepatosplenomegaly and "wrinkled tissue paper" appearance of macrophages. * **Sphingomyelinase:** Deficiency results in **Niemann-Pick Disease**, leading to sphingomyelin accumulation and foam cells. **Clinical Pearls for NEET-PG:** * **Presentation:** Symptoms appear shortly after starting milk feeds (lactose = glucose + galactose). Look for jaundice, hepatomegaly, infantile cataracts (due to galactitol), and failure to thrive. * **Sepsis Risk:** These infants have a significantly increased predisposition to **E. coli neonatal sepsis**. * **Diagnosis:** Reducing substances in urine (Clinitest positive) but a negative glucose oxidase test (Dipstick). * **Treatment:** Immediate and lifelong elimination of galactose and lactose from the diet.

Question 604: A 10-year-old child presents with aggressive, self-mutilating behavior, poor concentration, joint pain, and reduced urinary output. Deficiency of which enzyme is most likely responsible for this presentation?

A. Hypoxanthine-guanine phosphoribosyltransferase (HGPT) (Correct Answer)
B. Adenosine Deaminase
C. Alkaline Phosphatase (APase)
D. Acid Maltase

Explanation: ### Explanation The clinical presentation of **self-mutilation** (biting of lips and fingers), **aggressive behavior**, and signs of **hyperuricemia** (joint pain/gout and renal failure/reduced urinary output) is a classic triad for **Lesch-Nyhan Syndrome**. **1. Why Option A is Correct:** Lesch-Nyhan Syndrome is an X-linked recessive disorder caused by a deficiency of **Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)**. This enzyme is crucial for the **Purine Salvage Pathway**, where it converts hypoxanthine to IMP and guanine to GMP. Its deficiency leads to: * **Hyperuricemia:** Failure to salvage purines causes them to be degraded into excessive Uric Acid. * **Neurological Symptoms:** The brain relies heavily on the salvage pathway; low HGPRT levels lead to dopamine dysfunction, causing the characteristic self-mutilation and cognitive impairment. **2. Why Incorrect Options are Wrong:** * **B. Adenosine Deaminase (ADA):** Deficiency leads to **Severe Combined Immunodeficiency (SCID)** due to the accumulation of dATP, which is toxic to lymphocytes. It does not cause self-mutilation. * **C. Alkaline Phosphatase (APase):** Low levels are seen in Hypophosphatasia (bone mineralization defects), while high levels indicate liver or bone disease. * **D. Acid Maltase (α-1,4-glucosidase):** Deficiency causes **Pompe Disease** (Glycogen Storage Disease Type II), characterized by cardiomegaly and muscle weakness, not hyperuricemia. **3. NEET-PG High-Yield Pearls:** * **Inheritance:** X-linked Recessive (mostly affects males). * **Biochemical Hallmark:** Increased levels of **PRPP** (Phosphoribosyl pyrophosphate) and decreased IMP/GMP. * **Diagnosis:** "Orange sand" crystals (sodium urate) often found in the diapers of affected infants. * **Treatment:** Allopurinol or Febuxostat (manages uric acid but does not fix neurological symptoms).

Question 605: An infant presents with hepatomegaly, hypoglycemia, hyperlipidemia, and acidosis. What is the diagnosis?

A. Von Gierke's disease (Correct Answer)
B. Cori's disease
C. Pompe's disease
D. All of the above

Explanation: **Explanation:** The clinical presentation of hepatomegaly, hypoglycemia, hyperlipidemia, and acidosis is the classic "quadrad" of **Von Gierke’s Disease (GSD Type I)**. **1. Why Option A is Correct:** Von Gierke’s disease is caused by a deficiency of **Glucose-6-Phosphatase**. This enzyme is essential for the final step of both glycogenolysis and gluconeogenesis. Its absence leads to: * **Severe Fasting Hypoglycemia:** The liver cannot release free glucose into the blood. * **Hepatomegaly:** Excessive accumulation of glycogen (normal structure) in the liver. * **Lactic Acidosis:** Glucose-6-phosphate shunts into the glycolytic pathway, increasing lactate. * **Hyperlipidemia & Hyperuricemia:** Diverted metabolites lead to increased VLDL/triglycerides and purine degradation (Gout). **2. Why Other Options are Incorrect:** * **B. Cori’s Disease (GSD Type III):** Caused by **Debranching enzyme** deficiency. While it presents with hepatomegaly and hypoglycemia, the symptoms are generally milder, and **lactate levels are typically normal** because gluconeogenesis remains intact. * **C. Pompe’s Disease (GSD Type II):** Caused by **Lysosomal α-1,4-glucosidase** deficiency. It primarily affects the heart and muscles (**Cardiomegaly**), and notably, it does **not** present with hypoglycemia as glycogen mobilization in the liver is unaffected. **Clinical Pearls for NEET-PG:** * **"Doll-like facies"** (fatty cheeks) is a characteristic physical finding in Von Gierke’s. * **Hyperuricemia** in GSD Type I can lead to "Gouty arthritis" later in life. * **Treatment:** Frequent oral cornstarch (slow-release glucose) and avoidance of fructose/galactose.

Question 606: Lorenzo's oil is used in the treatment of which of the following conditions?

A. Gaucher disease
B. Adrenoleukodystrophy (Correct Answer)
C. Fabry's disease
D. Hurler disease

Explanation: **Explanation:** **Adrenoleukodystrophy (ALD)** is an X-linked recessive peroxisomal disorder caused by a mutation in the *ABCD1* gene. This defect leads to the impaired transport of **Very Long Chain Fatty Acids (VLCFA)** into peroxisomes for β-oxidation. Consequently, VLCFAs accumulate in the brain (causing demyelination) and the adrenal cortex (causing adrenal insufficiency). **Lorenzo’s Oil** is a 4:1 mixture of glyceryl trioleate and glyceryl trierucate. It works by competitively inhibiting the enzyme responsible for the elongation of saturated fatty acids, thereby lowering the levels of VLCFAs in the plasma. **Analysis of Incorrect Options:** * **Gaucher Disease:** A lysosomal storage disorder caused by a deficiency of **β-glucocerebrosidase**. Treatment involves Enzyme Replacement Therapy (ERT) with Imiglucerase. * **Fabry’s Disease:** An X-linked lysosomal storage disorder due to **α-galactosidase A** deficiency. Characterized by angiokeratomas and renal failure; treated with ERT (Agalsidase beta). * **Hurler Disease (MPS I):** A mucopolysaccharidosis caused by **α-L-iduronidase** deficiency, leading to the accumulation of dermatan and heparan sulfate. Treatment includes ERT and hematopoietic stem cell transplantation. **High-Yield Pearls for NEET-PG:** * **Zellweger Syndrome:** The most severe peroxisomal biogenesis disorder (empty peroxisomes); presents with "craniofacial dysmorphism" and hepatomegaly. * **Refsum Disease:** Defect in **α-oxidation** due to phytanoyl-CoA hydroxylase deficiency; requires restriction of chlorophyll/phytanic acid in the diet. * **VLCFA Oxidation:** Occurs exclusively in **peroxisomes**, whereas short, medium, and long-chain fatty acids are oxidized in the mitochondria.

Question 607: Which one of the following lysosomal storage disorders is associated with mental retardation?

A. Metachromatic leucodystrophy
B. Fabry's disease
C. Tay-Sachs disease
D. All of the above (Correct Answer)

Explanation: **Explanation:** Lysosomal Storage Disorders (LSDs) are metabolic diseases caused by the deficiency of specific lysosomal enzymes, leading to the accumulation of undigested substrates. When these substrates accumulate within the Central Nervous System (CNS), they typically manifest as progressive neurodegeneration and **mental retardation**. 1. **Metachromatic Leucodystrophy (MLD):** Caused by a deficiency of **Arylsulfatase A**, leading to the accumulation of cerebroside sulfate. This results in widespread demyelination of both the central and peripheral nervous systems, presenting clinically with cognitive decline (mental retardation), ataxia, and seizures. 2. **Fabry’s Disease:** Caused by a deficiency of **$\alpha$-galactosidase A** (X-linked recessive). While primarily known for angiokeratomas and renal failure, the accumulation of globotriaosylceramide in the vascular endothelium of the brain can lead to cognitive impairment and neuropsychiatric symptoms. 3. **Tay-Sachs Disease:** Caused by a deficiency of **Hexosaminidase A**, leading to $GM_2$ ganglioside accumulation. It is a classic neurodegenerative LSD characterized by developmental regression, severe mental retardation, and a "cherry-red spot" on the macula. **Clinical Pearls for NEET-PG:** * **Tay-Sachs vs. Niemann-Pick:** Both have a cherry-red spot, but **hepatosplenomegaly** is absent in Tay-Sachs and present in Niemann-Pick. * **Gaucher’s Disease:** The most common LSD; look for "crinkled paper" cytoplasm in macrophages. * **Hunter vs. Hurler:** Both are Mucopolysaccharidoses (MPS). **Hunter syndrome** is X-linked and lacks corneal clouding, whereas **Hurler syndrome** has corneal clouding. Both involve mental retardation. * **Rule of Thumb:** Most LSDs involving sphingolipidoses or MPS (except Sanfilippo) that affect the CNS will present with some degree of intellectual disability.

Question 608: Defective chromosome associated with DiGeorge syndrome is -

A. 7
B. 15
C. 17
D. 22 (Correct Answer)

Explanation: **Explanation:** **1. Why Option D (Chromosome 22) is Correct:** DiGeorge Syndrome (DGS) is caused by a microdeletion on the **long arm (q) of chromosome 22**, specifically at the **22q11.2** locus. This region contains the *TBX1* gene, which is critical for the normal development of the **3rd and 4th pharyngeal pouches**. Failure of these pouches to develop leads to the classic triad of thymic hypoplasia (T-cell deficiency), parathyroid hypoplasia (hypocalcemia), and conotruncal cardiac defects. **2. Why Other Options are Incorrect:** * **Option A (Chromosome 7):** Associated with **Williams Syndrome** (deletion at 7q11.23), characterized by "elfin" facies, hypercalcemia, and supravalvular aortic stenosis. * **Option B (Chromosome 15):** Associated with **Prader-Willi Syndrome** (paternal deletion) and **Angelman Syndrome** (maternal deletion) at the 15q11-q13 locus. * **Option C (Chromosome 17):** Associated with **Neurofibromatosis Type 1 (NF1)** and **Miller-Dieker Syndrome** (lissencephaly). **3. High-Yield Clinical Pearls for NEET-PG:** * **CATCH-22 Mnemonic:** **C**ardiac defects (Truncus arteriosus, TOF), **A**bnormal facies, **T**hymic aplasia, **C**left palate, **H**ypocalcemia/Hypoparathyroidism, due to **22**q11 deletion. * **Diagnosis:** The gold standard for detecting this microdeletion is **FISH** (Fluorescence In Situ Hybridization). * **Velocardiofacial Syndrome:** This is a related spectrum disorder also caused by the 22q11.2 deletion, primarily featuring cleft palate and cardiac defects. * **Biochemical Hallmark:** Refractory neonatal seizures due to **hypocalcemia** (secondary to absent parathyroid glands).

Question 609: All of the following are Glycoproteinoses, EXCEPT?

A. Fucosidosis
B. Sanfilippo A syndrome (Correct Answer)
C. Sialidosis
D. a-mannosidosis

Explanation: **Explanation:** The core of this question lies in distinguishing between **Glycoproteinoses** and **Mucopolysaccharidoses (MPS)**. Both are sub-categories of Lysosomal Storage Disorders (LSDs), but they differ in the substrate that accumulates due to enzyme deficiencies. **Why Sanfilippo A syndrome is the correct answer:** Sanfilippo A syndrome (MPS III A) is a **Mucopolysaccharidosis**. It is caused by a deficiency in the enzyme *Heparan N-sulfatase*, leading to the accumulation of **Heparan sulfate** (a glycosaminoglycan or GAG). Unlike glycoproteinoses, MPS disorders primarily involve the inability to degrade long chains of sugar molecules found in connective tissues. **Why the other options are Glycoproteinoses:** Glycoproteinoses are characterized by the defective degradation of the oligosaccharide side chains of glycoproteins. * **Fucosidosis (Option A):** Deficiency of *α-L-fucosidase* leads to the accumulation of fucose-containing glycoconjugates. * **Sialidosis (Option C):** Also known as Mucolipidosis I, it is caused by a deficiency of *Neuraminidase (Sialidase)*, leading to the accumulation of sialic acid-rich compounds. * **α-mannosidosis (Option D):** Caused by a deficiency of *α-mannosidase*, resulting in the accumulation of mannose-rich oligosaccharides. **High-Yield Clinical Pearls for NEET-PG:** * **Sanfilippo Syndrome (MPS III):** Characterized by **severe CNS degeneration** and behavioral issues, but notably has **mild physical/skeletal changes** compared to Hurler or Hunter syndromes. * **Cherry Red Spot:** Seen in Sialidosis (Type I), similar to Tay-Sachs and Niemann-Pick disease. * **Aspartylglucosaminuria:** Another high-yield example of a Glycoproteinosis often tested alongside those listed above. * **Inheritance:** Most LSDs are Autosomal Recessive, **EXCEPT Hunter syndrome and Fabry disease**, which are X-linked Recessive.

Question 610: Which of the following is true about mitochondrial inheritance?

A. An offspring born to an affected male will be affected.
B. An offspring born to an affected female will be affected. (Correct Answer)
C. An offspring born to an affected female will be normal.
D. All of the above.

Explanation: **Explanation:** Mitochondrial inheritance (also known as maternal inheritance) follows a non-Mendelian pattern because mitochondria are inherited exclusively from the mother. During fertilization, the sperm contributes only its nuclear DNA, while the ovum provides the cytoplasm and all the organelles, including the mitochondria. **1. Why Option B is correct:** Since the mitochondrial genome is transmitted only through the oocyte, an affected mother will pass the defective mitochondrial DNA (mtDNA) to **all** of her offspring (both sons and daughters). Therefore, offspring born to an affected female will be affected. **2. Why other options are incorrect:** * **Option A:** An affected male cannot transmit the disease to his children because paternal mitochondria in the sperm tail are typically degraded or excluded during fertilization. * **Option C:** This contradicts the fundamental principle of maternal transmission. Unless there is a rare case of paternal leakage (clinically negligible for exams), the offspring of an affected female will inherit the mutation. **Clinical Pearls for NEET-PG:** * **Heteroplasmy:** This is a key concept where a cell contains a mixture of both mutant and normal mtDNA. The severity of the disease depends on the ratio of mutant to normal mitochondria (Threshold effect). * **High-Yield Examples:** * **LHON** (Leber’s Hereditary Optic Neuropathy): Sudden painless loss of vision. * **MELAS** (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). * **MERRF** (Myoclonic Epilepsy with Ragged Red Fibers). * **Tissues Affected:** Mitochondrial diseases primarily affect high-energy demanding tissues like the CNS, skeletal muscle, and heart.

Practice by Chapter

Single Gene Disorders

Practice Questions

Biochemical Diagnosis of Genetic Disorders

Practice Questions

Inborn Errors of Metabolism

Practice Questions

Lysosomal Storage Diseases

Practice Questions

Glycogen Storage Diseases

Practice Questions

Disorders of Lipoprotein Metabolism

Practice Questions

Disorders of Purine and Pyrimidine Metabolism

Practice Questions

Hemoglobinopathies

Practice Questions

Porphyrias

Practice Questions

Biochemical Markers for Disease Diagnosis

Practice Questions

Newborn Screening for Genetic Disorders

Practice Questions

Enzyme Replacement Therapy

Practice Questions

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