Genetic Disorders and Biochemical Pathology — MCQs

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

Question 341: What is true about Fragile X syndrome?

A. Involves a triplet nucleotide repeat sequence (Correct Answer)
B. Characterized by chromosomal breaking
C. Caused by a mitochondrial mutation
D. Absence of a centrochrome

Explanation: **Explanation:** **Fragile X Syndrome (FXS)** is the most common cause of inherited intellectual disability and the second most common genetic cause of intellectual disability after Down syndrome. **1. Why Option A is Correct:** Fragile X syndrome is a classic example of a **Trinucleotide Repeat Expansion disorder**. It is caused by the expansion of the **CGG repeat** in the 5' untranslated region of the ***FMR1* gene** located on the X chromosome. * **Normal:** <55 repeats. * **Full Mutation:** >200 repeats. This expansion leads to **hypermethylation** of the promoter region, effectively silencing the gene and resulting in a deficiency of the Fragile X Mental Retardation Protein (FMRP), which is essential for normal brain development. **2. Why Other Options are Incorrect:** * **Option B:** While the name "Fragile X" comes from the appearance of a "broken" or constricted site on the X chromosome when cultured in folate-deficient medium, there is no actual **chromosomal breaking** or instability in vivo. It is a gene mutation, not a breakage syndrome like Fanconi anemia. * **Option C:** FXS follows an **X-linked dominant** inheritance pattern with variable expressivity (anticipation), not mitochondrial inheritance. * **Option D:** "Centrochrome" is not a standard biological term relevant to this pathology. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Triad:** Intellectual disability, **Macroorchidism** (enlarged testes, post-pubertal), and long face with large everted ears. * **Genetics:** Shows **Anticipation** (severity increases in successive generations) and the **Sherman Paradox**. * **Diagnosis:** PCR or Southern Blot (to detect repeat size). * **Behavioral:** Highly associated with Autism Spectrum Disorder (ASD) and ADHD.

Question 342: All of the following are disorders due to peroxisomal abnormalities except?

A. Pfeiffer syndrome (Correct Answer)
B. Zellweger syndrome
C. Hyperoxaluria type 1
D. Acatalasemia

Explanation: **Explanation:** The correct answer is **Pfeiffer syndrome** because it is a genetic disorder caused by mutations in the **Fibroblast Growth Factor Receptor (FGFR1 or FGFR2)** genes, not peroxisomal dysfunction. It is characterized by craniosynostosis (premature fusion of skull bones), midface hypoplasia, and broad thumbs/great toes. **Analysis of Peroxisomal Disorders (Incorrect Options):** * **Zellweger Syndrome:** This is the most severe **Peroxisomal Biogenesis Disorder (PBD)**. It results from mutations in *PEX* genes, leading to the failure to import proteins into peroxisomes ("empty" peroxisomes). Clinical features include craniofacial dysmorphism, hypotonia, and seizures. * **Hyperoxaluria Type 1:** This is a **peroxisomal enzyme deficiency**. It is caused by a deficiency of the liver-specific peroxisomal enzyme *alanine-glyoxylate aminotransferase (AGT)*. This leads to excessive oxalate production, resulting in recurrent nephrolithiasis and systemic oxalosis. * **Acatalasemia:** This is an autosomal recessive condition characterized by a deficiency of **catalase**, a key antioxidant enzyme located within peroxisomes that breaks down hydrogen peroxide. **High-Yield NEET-PG Pearls:** * **Peroxisome Functions:** Beta-oxidation of Very Long Chain Fatty Acids (VLCFA), plasmalogen synthesis (essential for myelin), and bile acid synthesis. * **Refsum Disease:** Another high-yield peroxisomal disorder caused by a deficiency in alpha-oxidation (Phytanoyl-CoA hydroxylase deficiency), leading to the accumulation of phytanic acid. * **X-linked Adrenoleukodystrophy (X-ALD):** Caused by a defect in the *ABCD1* transporter, preventing VLCFA entry into peroxisomes for oxidation.

Question 343: Which condition is caused by a deficiency of fibrillin 1?

A. Marfan syndrome (Correct Answer)
B. Ehlers-Danlos syndrome
C. Osteogenesis imperfecta
D. Angelman syndrome

Explanation: **Explanation:** **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 glycoprotein that serves as a major structural component of extracellular microfibrils. These microfibrils provide a scaffold for elastin deposition and regulate **TGF-β (Transforming Growth Factor beta)** signaling. A deficiency leads to weakened connective tissue and excessive TGF-β activation, resulting in the characteristic skeletal, ocular, and cardiovascular manifestations. **Analysis of Incorrect Options:** * **Ehlers-Danlos syndrome:** This is a heterogeneous group of disorders primarily caused by defects in the synthesis or structure of **fibrillar collagen** (e.g., Type V collagen in the Classical type, Type III in the Vascular type), not fibrillin. * **Osteogenesis imperfecta:** Also known as "brittle bone disease," it is most commonly caused by mutations in the genes encoding **Type I collagen** (COL1A1 and COL1A2). * **Angelman syndrome:** This is a neurogenetic disorder caused by the loss of function of the **UBE3A gene** on chromosome 15 (maternal inheritance/imprinting), unrelated to structural proteins or connective tissue. **High-Yield Clinical Pearls for NEET-PG:** * **Cardiovascular:** The most common cause of death is **Aortic Root Dilatation** leading to aortic dissection or aneurysm. Mitral Valve Prolapse (MVP) is also frequent. * **Ocular:** Characterized by **Ectopia lentis** (dislocation of the lens), typically **upward and outward** (superior subluxation). * **Skeletal:** Tall stature, arachnodactyly (long fingers), pectus excavatum, and a high-arched palate. * **Mnemonic:** Marfan = **M**utation in **F**ibrillin-1 on chromosome **15** (Fifteen/Fibrillin).

Question 344: Which glycosaminoglycan is affected in Sanfilippo syndromes?

A. Dermatan sulfate
B. Heparan sulfate (Correct Answer)
C. Keratan sulfate
D. Chondroitin sulfate

Explanation: ### Explanation **Sanfilippo Syndrome (Mucopolysaccharidosis Type III)** is a lysosomal storage disorder characterized by the body's inability to break down **Heparan sulfate**. This occurs due to a deficiency in one of four enzymes required for its degradation (Types A, B, C, and D). #### Why Heparan Sulfate is Correct: Heparan sulfate is a glycosaminoglycan (GAG) primarily found in the extracellular matrix and on cell surfaces, particularly in the CNS. In Sanfilippo syndrome, the accumulation of partially degraded heparan sulfate leads to severe progressive **neurodegeneration**, which is the clinical hallmark of this specific MPS type. #### Why Other Options are Incorrect: * **Dermatan sulfate:** This GAG accumulates in **Hurler (MPS I)** and **Hunter (MPS II)** syndromes. Its accumulation is typically associated with coarse facial features, hepatosplenomegaly, and valvular heart disease. * **Keratan sulfate:** This is the primary GAG affected in **Morquio syndrome (MPS IV)**. Clinical presentation involves severe skeletal dysplasia (dysostosis multiplex) without significant intellectual disability. * **Chondroitin sulfate:** While found in many tissues, it is specifically elevated alongside keratan sulfate in Morquio syndrome. It is not the primary diagnostic marker for Sanfilippo. #### NEET-PG High-Yield Pearls: * **Clinical Triad of Sanfilippo:** Severe developmental delay/regression, hyperactivity/behavioral issues, and relatively mild physical (somatic) features compared to Hurler syndrome. * **Enzyme Deficiency:** The most common and severe form is **Type A** (Heparan N-sulfatase deficiency). * **Inheritance:** All Mucopolysaccharidoses are **Autosomal Recessive**, *except* Hunter Syndrome (MPS II), which is **X-linked Recessive**. * **Corneal Clouding:** Notably **absent** in Sanfilippo and Hunter syndromes (a common exam differentiator).

Question 345: McArdle’s disease is caused due to a deficiency of which enzyme?

A. Glucose-6-phosphatase
B. Muscle (Myo) Phosphorylase (Correct Answer)
C. Lysosomal glucosidase
D. Microsomal Pi transporter

Explanation: **Explanation:** **McArdle’s Disease (Glycogen Storage Disease Type V)** is an autosomal recessive disorder caused by a deficiency of **Muscle Phosphorylase (Myophosphorylase)**. This enzyme is responsible for the rate-limiting step of glycogenolysis in skeletal muscle, breaking down glycogen into glucose-1-phosphate. Without it, muscles cannot mobilize glucose during anaerobic exercise, leading to an energy crisis. **Analysis of Options:** * **Option B (Correct):** Muscle Phosphorylase deficiency prevents glycogen breakdown in muscles. Clinically, this manifests as exercise intolerance, muscle cramps, and myoglobinuria following strenuous activity. * **Option A (Incorrect):** **Glucose-6-phosphatase** deficiency causes **Von Gierke’s Disease (GSD Type I)**. It primarily affects the liver and kidneys, leading to severe fasting hypoglycemia and hepatomegaly. * **Option C (Incorrect):** **Lysosomal α-1,4-glucosidase (Acid Maltase)** deficiency causes **Pompe’s Disease (GSD Type II)**. It results in glycogen accumulation in lysosomes, primarily affecting the heart (cardiomegaly) and skeletal muscles. * **Option D (Incorrect):** Deficiency of the **Microsomal Pi (Inorganic Phosphate) transporter** is associated with **GSD Type Ic**, a variant of Von Gierke’s disease. **High-Yield Clinical Pearls for NEET-PG:** * **"Second Wind" Phenomenon:** A classic feature of McArdle’s where patients experience relief from fatigue after a few minutes of exercise as the body switches to using free fatty acids and blood glucose. * **Ischemic Forearm Test:** Patients with McArdle’s show a **failure of blood lactate to rise** after exercise (since they cannot break down glycogen to lactate), but ammonia levels will rise. * **Burgundy-colored urine:** Post-exercise myoglobinuria can lead to acute renal failure in severe cases.

Question 346: A child presents with hypotonia and seizures, confirmed to be cerebrohepatorenal syndrome. Which of the following is accumulated in the brain in cerebrohepatorenal syndrome?

A. Glucose
B. Long chain fatty acid (Correct Answer)
C. Triglycerides
D. Lactic acid

Explanation: **Explanation:** **Cerebrohepatorenal syndrome**, also known as **Zellweger Syndrome**, is the most severe form of peroxisomal biogenesis disorders. It is caused by mutations in *PEX* genes, which are essential for the normal assembly and function of peroxisomes. **Why the correct answer is right:** Peroxisomes are the primary site for the **$\beta$-oxidation of Very Long Chain Fatty Acids (VLCFA)**—fatty acids with 22 or more carbons. In Zellweger syndrome, the absence of functional peroxisomes leads to a failure in breaking down these lipids. Consequently, **VLCFAs (specifically C24 and C26)** accumulate in the blood and tissues, particularly the brain (causing demyelination and seizures) and the liver (causing hepatomegaly and jaundice). **Why the incorrect options are wrong:** * **A. Glucose:** Glucose metabolism occurs primarily in the cytosol and mitochondria. While hypoglycemia can occur in liver failure, glucose does not "accumulate" as a pathological hallmark of this syndrome. * **C. Triglycerides:** These are stored in adipose tissue and processed via lipolysis. Their accumulation is characteristic of conditions like Wolman disease or simple steatosis, not peroxisomal disorders. * **D. Lactic acid:** Lactic acidosis is a hallmark of mitochondrial disorders (e.g., MELAS) or defects in the Pyruvate Dehydrogenase complex, not peroxisomal biogenesis. **High-Yield Clinical Pearls for NEET-PG:** * **Triad of Zellweger:** Hypotonia (floppy baby), Seizures, and Hepatomegaly. * **Dysmorphism:** Look for a high forehead, large anterior fontanelle, and "stippled epiphyses" (chondrodysplasia punctata) on X-ray. * **Biochemical Marker:** Elevated plasma levels of **VLCFA** is the definitive diagnostic test. * **Prognosis:** Usually fatal within the first year of life.

Question 347: Lysosomal accumulation of sphingomyelin is seen in which of the following conditions?

A. Niemann-Pick disease (Correct Answer)
B. Farber's disease
C. Tay-Sachs disease
D. Krabbe's disease

Explanation: **Explanation:** The correct answer is **Niemann-Pick disease**. This condition is a lysosomal storage disorder caused by a deficiency of the enzyme **acid sphingomyelinase**. This enzyme is responsible for the hydrolysis of sphingomyelin into ceramide and phosphorylcholine. When deficient, **sphingomyelin accumulates** within the lysosomes of cells, particularly in the reticuloendothelial system (liver, spleen, and bone marrow) and the central nervous system. **Analysis of Options:** * **Farber’s disease:** Characterized by a deficiency of **acid ceramidase**, leading to the accumulation of **ceramide**. Clinical hallmarks include painful joint swelling and subcutaneous nodules. * **Tay-Sachs disease:** Caused by a deficiency of **Hexosaminidase A**, resulting in the accumulation of **GM2 ganglioside**. It presents with a cherry-red spot on the macula but lacks hepatosplenomegaly. * **Krabbe’s disease:** Caused by a deficiency of **galactocerebrosidase**, leading to the accumulation of **galactocerebroside** and psychosine, which is toxic to myelin-producing cells. **High-Yield Clinical Pearls for NEET-PG:** * **Histology:** Niemann-Pick is associated with **"Foam cells"** (lipid-laden macrophages) in the bone marrow. * **Clinical Triad:** Look for hepatosplenomegaly, progressive neurodegeneration, and a **cherry-red spot** on the macula (Type A). * **Differentiator:** Unlike Gaucher’s disease, Niemann-Pick features a cherry-red spot. Unlike Tay-Sachs, Niemann-Pick features **hepatosplenomegaly**. * **Genetics:** Most sphingolipidoses are Autosomal Recessive (except Fabry’s, which is X-linked Recessive).

Question 348: A 2-year-old child presents with failure to thrive, progressive neurologic deterioration including deafness and blindness, hepatosplenomegaly, and a cherry-red spot on funduscopic examination. What is the most likely diagnosis?

A. Hunter syndrome
B. Niemann-Pick disease (Correct Answer)
C. Pompe's disease
D. Tyrosinosis

Explanation: ### Explanation **Correct Answer: B. Niemann-Pick disease** **1. Why Niemann-Pick Disease is Correct:** Niemann-Pick disease (Type A) is a lysosomal storage disorder caused by a deficiency of **sphingomyelinase**, leading to the accumulation of sphingomyelin. The clinical triad of **progressive neurodegeneration**, **hepatosplenomegaly**, and a **cherry-red spot** on the macula is classic. While Tay-Sachs disease also presents with a cherry-red spot and neurodegeneration, the presence of **hepatosplenomegaly** is the key clinical differentiator that points specifically to Niemann-Pick. **2. Analysis of Incorrect Options:** * **A. Hunter Syndrome:** A mucopolysaccharidosis (MPS II) characterized by coarse facies, hepatosplenomegaly, and aggressive behavior. Crucially, it lacks a cherry-red spot and, unlike Hurler syndrome, does *not* have corneal clouding. * **C. Pompe’s Disease:** A glycogen storage disease (Type II) due to acid maltase deficiency. It primarily presents with severe **cardiomegaly**, hypotonia ("floppy baby"), and heart failure, but not a cherry-red spot. * **D. Tyrosinosis (Tyrosinemia Type I):** Caused by a deficiency of fumarylacetoacetate hydrolase. It presents with liver failure, rickets, and a "cabbage-like" odor, but not the neuro-ophthalmologic findings described. **3. NEET-PG High-Yield Pearls:** * **Cherry-red spot differential:** Remember the mnemonic **"SACHET"**: **S**andhoff disease, **A**maurotic familial idiocy (Tay-Sachs), **C**herry-red spot myoclonus syndrome (Sialidosis), **H**urler syndrome (rarely), **E**n central retinal artery occlusion, **T**ay-Sachs/Niemann-Pick. * **Histology:** Niemann-Pick is associated with **"Foam cells"** (lipid-laden macrophages) in the bone marrow. * **Tay-Sachs vs. Niemann-Pick:** * *Tay-Sachs:* No hepatosplenomegaly (Hexosaminidase A deficiency). * *Niemann-Pick:* Hepatosplenomegaly present (Sphingomyelinase deficiency).

Question 349: A child presented with deranged developmental milestones and hyperactivity, later developed self-mutilating behavior and hair-pulling behavior, and died a few years later. Which enzyme deficiency is most likely implicated?

A. Phenylalanine hydroxylase
B. Hypoxanthine-guanine phosphoribosyltransferase (HGPT) (Correct Answer)
C. Adenosine deaminase
D. Hexosaminidase A

Explanation: ### Explanation The clinical presentation of developmental delay, hyperactivity, and the hallmark sign of **self-mutilating behavior** (biting lips/fingers) and hair-pulling (trichotillomania) is classic for **Lesch-Nyhan Syndrome**. **1. Why the Correct Answer is Right:** 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: * **Excessive Uric Acid:** Failure to salvage purines leads to their degradation into uric acid (Hyperuricemia). * **Neurological Dysfunction:** Low levels of dopamine in the basal ganglia (due to impaired purine recycling) result in choreoathetosis and the characteristic compulsive self-mutilation. **2. Why the Incorrect Options are Wrong:** * **Phenylalanine hydroxylase (Option A):** Deficiency causes **Phenylketonuria (PKU)**. While it presents with developmental delay and hyperactivity, it is characterized by a "mousy odor," hypopigmentation, and seizures, not self-mutilation. * **Adenosine deaminase (Option B):** Deficiency leads to **Severe Combined Immunodeficiency (SCID)**. It presents with recurrent infections and failure to thrive due to lymphotoxicity, not behavioral or neurological symptoms. * **Hexosaminidase A (Option C):** Deficiency causes **Tay-Sachs Disease**. It presents with neurodegeneration, "cherry-red spot" on the macula, and exaggerated startle response, but lacks self-mutilation. **3. NEET-PG High-Yield Pearls:** * **Mnemonic for HGPRT:** **H**yperuricemia, **G**out, **P**issed off (aggression/self-mutilation), **R**etardation, **T**one (dystonia). * **Diagnosis:** Elevated serum uric acid and "orange sand" (sodium urate crystals) in the diaper. * **Treatment:** Allopurinol or Febuxostat (manages hyperuricemia but does not fix neurological symptoms).

Question 350: Which chromosomal compliment is associated with Turner syndrome?

A. Turner syndrome (Correct Answer)
B. Edward syndrome
C. Patau syndrome
D. Klinefelter syndrome

Explanation: **Explanation:** **Turner Syndrome (45, XO)** is the correct answer. It is a form of gonadal dysgenesis caused by the complete or partial absence of one X chromosome in females. This occurs most commonly due to **nondisjunction** during paternal meiosis. The lack of the second sex chromosome leads to the characteristic "streak ovaries" and a deficiency in estrogen. **Analysis of Incorrect Options:** * **Edward Syndrome (Trisomy 18):** This is an autosomal chromosomal disorder characterized by an extra copy of chromosome 18. Key features include "rocker-bottom" feet, micrognathia, and clenched fists with overlapping fingers. * **Patau Syndrome (Trisomy 13):** This involves an extra copy of chromosome 13. It presents with severe midline defects such as holoprosencephaly, cleft lip/palate, and polydactyly. * **Klinefelter Syndrome (47, XXY):** This is a male chromosomal disorder where there is at least one extra X chromosome. It presents with testicular atrophy, gynecomastia, and a tall, eunuchoid body habitus. **High-Yield Clinical Pearls for NEET-PG:** * **Most common cause of primary amenorrhea:** Turner Syndrome. * **Cardiovascular associations:** Bicuspid aortic valve (most common) and Coarctation of the aorta. * **Physical findings:** Webbed neck (cystic hygroma), short stature, and widely spaced nipples (shield chest). * **Renal anomaly:** Horseshoe kidney. * **Biochemical profile:** Elevated LH and FSH (Hypergonadotropic hypogonadism) due to lack of feedback inhibition from estrogen.

Practice by Chapter

Single Gene Disorders

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Biochemical Diagnosis of Genetic Disorders

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Inborn Errors of Metabolism

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Lysosomal Storage Diseases

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Glycogen Storage Diseases

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Disorders of Lipoprotein Metabolism

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Disorders of Purine and Pyrimidine Metabolism

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Hemoglobinopathies

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Porphyrias

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Biochemical Markers for Disease Diagnosis

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Newborn Screening for Genetic Disorders

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Enzyme Replacement Therapy

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