Genetic Disorders and Biochemical Pathology — MCQs

An infant appears normal at birth following an uncomplicated pregnancy and begins to nurse. Within 3 days the infant exhibits vomiting and diarrhea. A week later jaundice is evident, and the infant becomes febrile. On physical examination hepatomegaly is present. Laboratory studies show abnormal reducing substances in the urine, and Escherichia coli is cultured from blood. This infant most likely has a deficiency in which of the following enzymes?

Q434Medium

A 25-year-old male presented with complaints of bilateral knee, hip joints, and lower spine pain. On examination, the joints were erythematous and tender. Dark black spots were noted on the sclera and ear cartilage. X-rays of the affected joints were taken. Which of the following drugs has been approved for this condition?

Q435Easy

Homogentisate oxidase deficiency causes which of the following conditions?

Q436Easy

Which one of the following is not a feature of Phenylketonuria?

Q437Easy

Classical type of galactosemia is due to deficiency of which enzyme?

Q438Medium

All of the following are X-linked recessive disorders except?

Q439Easy

Which of the following are characteristic features of Myophosphorylase deficiency?

Q440Medium

An infant is brought to a hospital because her wet diapers turn black when they are exposed to air. Physical examination is normal. Urine is positive both for reducing substance and when tested with ferric chloride. This disorder is caused by a deficiency of which of the following enzymes?

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

Question 431: Which of the following diseases exhibits pleiotropism?

A. Marfan syndrome
B. Sickle cell disease
C. Phenylketonuria
D. All of the above (Correct Answer)

Explanation: **Explanation:** **Pleiotropism** is a genetic phenomenon where a **single gene mutation** results in multiple, seemingly unrelated phenotypic effects across different organ systems. **Why "All of the above" is correct:** All three listed conditions are classic examples of pleiotropy: * **Marfan Syndrome:** A mutation in the *FBN1* gene (encoding Fibrillin-1) affects connective tissue globally. This leads to diverse clinical features: skeletal (tall stature, arachnodactyly), ocular (ectopia lentis), and cardiovascular (aortic aneurysm/dissection). * **Sickle Cell Disease:** A single point mutation in the $\beta$-globin gene causes hemoglobin polymerization. This leads to a cascade of effects: chronic anemia, splenic infarction, painful vaso-occlusive crises, and kidney damage. * **Phenylketonuria (PKU):** A deficiency in the enzyme *Phenylalanine Hydroxylase* leads to toxic accumulation of phenylalanine. This manifests as intellectual disability, reduced hair/skin pigmentation (due to decreased melanin), and a characteristic "mousy" body odor. **Clinical Pearls for NEET-PG:** * **Pleiotropy vs. Polygenic:** Pleiotropy is *one gene $\rightarrow$ many traits*. Polygenic inheritance is *many genes $\rightarrow$ one trait* (e.g., height, skin color). * **Variable Expressivity:** This refers to the *severity* of the phenotype among individuals with the same genotype (common in Marfan syndrome). * **High-Yield Example:** **Cystic Fibrosis** is another frequently tested pleiotropic condition (affects lungs, pancreas, and sweat glands). * **Dominant Negative Effect:** Marfan syndrome is also an example of a dominant negative mutation, where the abnormal protein disrupts the function of the normal protein product.

Question 432: In Crigler-Najjar syndrome type II, what is the primary defect?

A. Uptake of bilirubin by liver cells
B. Conjugation of bilirubin (Correct Answer)
C. Excretion of bilirubin
D. Bile duct obstruction preventing bile passage into the intestine

Explanation: **Explanation:** Crigler-Najjar syndrome (Type I and II) is a genetic disorder characterized by non-hemolytic unconjugated hyperbilirubinemia. The primary defect lies in the **conjugation of bilirubin** due to a deficiency of the enzyme **UDP-glucuronosyltransferase (UGT1A1)**. In Type II (Arias Syndrome), there is a partial deficiency (enzyme activity is typically <10% of normal), whereas Type I involves a complete absence of the enzyme. **Analysis of Options:** * **Option B (Correct):** Bilirubin must be conjugated with glucuronic acid by UGT1A1 to become water-soluble. A defect in this enzyme prevents conjugation, leading to a buildup of indirect (unconjugated) bilirubin. * **Option A:** Defective uptake of bilirubin by hepatocytes is characteristic of **Gilbert Syndrome** (which also involves UGT deficiency but to a lesser extent) and potentially certain drug interferences, but it is not the primary pathology of Crigler-Najjar. * **Option C:** Defective excretion of conjugated bilirubin into the bile canaliculi is seen in **Dubin-Johnson** and **Rotor syndromes**, which present with conjugated hyperbilirubinemia. * **Option D:** Bile duct obstruction causes **obstructive (post-hepatic) jaundice**, characterized by elevated conjugated bilirubin and alkaline phosphatase, not a genetic conjugation defect. **High-Yield Clinical Pearls for NEET-PG:** * **Type I vs. Type II:** Type I is severe, presents in neonates, and does not respond to Phenobarbital. Type II is milder and **responds to Phenobarbital**, which induces the remaining UGT1A1 enzyme activity. * **Kernicterus:** Highly likely in Type I due to very high unconjugated bilirubin; rare in Type II. * **Inheritance:** Type I is Autosomal Recessive; Type II is usually Autosomal Dominant with variable penetrance.

Question 433: An infant appears normal at birth following an uncomplicated pregnancy and begins to nurse. Within 3 days the infant exhibits vomiting and diarrhea. A week later jaundice is evident, and the infant becomes febrile. On physical examination hepatomegaly is present. Laboratory studies show abnormal reducing substances in the urine, and Escherichia coli is cultured from blood. This infant most likely has a deficiency in which of the following enzymes?

A. Galactose-1-phosphate uridyltransferase (Correct Answer)
B. Glucocerebrosidase
C. Phenylalanine hydroxylase
D. Sphingomyelinase

Explanation: ### **Explanation** The clinical presentation describes **Classic Galactosemia**, a medical emergency in neonates. **1. Why Galactose-1-phosphate uridyltransferase (GALT) is correct:** Classic Galactosemia (Type 1) is caused by a deficiency of the **GALT enzyme**. When the infant begins nursing (breast milk contains lactose, which is broken down into glucose and galactose), galactose cannot be converted to glucose-1-phosphate. This leads to the toxic accumulation of **galactose-1-phosphate** and **galactitol** in tissues. * **Clinical Triad:** Liver failure (jaundice, hepatomegaly), cataracts, and intellectual disability. * **Key Diagnostic Clues:** The presence of **reducing substances in urine** (non-glucose) and a high risk of **E. coli sepsis** (due to inhibition of leucocyte bactericidal activity by galactose metabolites). **2. Why the other options are incorrect:** * **B. Glucocerebrosidase:** Deficiency causes **Gaucher disease**. It presents with hepatosplenomegaly and bone pain, but not typically in the first week of life with vomiting and sepsis. * **C. Phenylalanine hydroxylase:** Deficiency causes **Phenylketonuria (PKU)**. It presents later with intellectual disability and a "mousy" odor, but does not cause acute jaundice or reducing substances in urine. * **D. Sphingomyelinase:** Deficiency causes **Niemann-Pick disease**. It presents with neurodegeneration and hepatosplenomegaly (Cherry-red spot on macula), but not acute neonatal metabolic crisis. **3. High-Yield Clinical Pearls for NEET-PG:** * **Initial Screening:** Reducing sugar in urine (Benedict’s test positive) but glucose oxidase stick (Dipstick) negative. * **Sepsis:** *E. coli* is the most common organism associated with Galactosemia. * **Treatment:** Immediate withdrawal of milk; switch to soy-based or lactose-free formula. * **Cataracts:** Formed due to the accumulation of **Galactitol** in the lens via the enzyme Aldose Reductase.

Question 434: A 25-year-old male presented with complaints of bilateral knee, hip joints, and lower spine pain. On examination, the joints were erythematous and tender. Dark black spots were noted on the sclera and ear cartilage. X-rays of the affected joints were taken. Which of the following drugs has been approved for this condition?

A. Nitisinone (Correct Answer)
B. Ceftriaxone
C. Nicotinamide
D. Bortezomib

Explanation: ### Explanation **Diagnosis: Alkaptonuria** The clinical triad of **large joint arthritis** (ochronotic arthropathy), **dark pigmentation of the sclera and ear cartilage** (ochronosis), and the history of dark spots suggests Alkaptonuria. This is an autosomal recessive disorder caused by a deficiency of the enzyme **Homogentisate 1,2-dioxygenase**, leading to the accumulation of **Homogentisic Acid (HGA)**. HGA oxidizes to form a melanin-like polymer that deposits in connective tissues. **1. Why Nitisinone is correct:** **Nitisinone (Orfadin)** is a competitive inhibitor of the enzyme **4-hydroxyphenylpyruvate dioxygenase**. By inhibiting this upstream enzyme in the tyrosine catabolic pathway, it prevents the formation and subsequent accumulation of Homogentisic Acid. It was recently approved (by the EMA/FDA) as the first disease-modifying treatment for Alkaptonuria to slow the progression of ochronosis and arthropathy. **2. Why the other options are incorrect:** * **Ceftriaxone:** A third-generation cephalosporin used for bacterial infections (e.g., septic arthritis or Lyme disease), which does not fit the chronic pigmentary presentation. * **Nicotinamide:** Vitamin B3, used to treat Pellagra (Dermatitis, Diarrhea, Dementia). * **Bortezomib:** A proteasome inhibitor used in the treatment of Multiple Myeloma. **3. High-Yield Clinical Pearls for NEET-PG:** * **Classic Sign:** Urine turns black upon standing or alkalinization (due to oxidation of HGA). * **Biochemical Pathway:** Phenylalanine → Tyrosine → 4-Hydroxyphenylpyruvate → **Homogentisic Acid** →(Homogentisate Oxidase)→ Maleylacetoacetate. * **Radiology:** X-rays typically show **intervertebral disc calcification** and narrowing (wafer-like calcification), which is a hallmark of Alkaptonuria. * **Dietary Management:** Restriction of Phenylalanine and Tyrosine intake.

Question 435: Homogentisate oxidase deficiency causes which of the following conditions?

A. Phenylketonuria
B. Alkaptonuria (Correct Answer)
C. Methylmalonic aciduria
D. Albinism

Explanation: ### Explanation **Correct Answer: B. Alkaptonuria** Alkaptonuria is an autosomal recessive disorder caused by a deficiency of the enzyme **Homogentisate 1,2-dioxygenase (Homogentisate oxidase)**. This enzyme is essential in the catabolic pathway of phenylalanine and tyrosine, where it converts homogentisic acid (HGA) into maleylacetoacetate. When deficient, HGA accumulates in the body and is excreted in the urine. Upon exposure to air, HGA undergoes oxidation and polymerization to form a melanin-like pigment, causing the urine to turn **black**. **Analysis of Incorrect Options:** * **A. Phenylketonuria (PKU):** Caused by a deficiency of **Phenylalanine hydroxylase** (or rarely, Dihydrobiopterin reductase), leading to the accumulation of phenylalanine. * **C. Methylmalonic aciduria:** Results from a deficiency of **Methylmalonyl-CoA mutase** or a defect in Vitamin B12 metabolism, leading to the accumulation of methylmalonic acid. * **D. Albinism:** Most commonly caused by a deficiency of the enzyme **Tyrosinase**, which is required for the conversion of tyrosine to melanin. **High-Yield Clinical Pearls for NEET-PG:** * **Ochronosis:** The deposition of dark pigment in connective tissues (cartilage, sclera, skin) is a hallmark of Alkaptonuria, typically appearing in the 3rd or 4th decade of life. * **Ochronotic Arthritis:** Long-term accumulation of HGA in large joints (spine, hips, knees) leads to severe degenerative arthritis. * **Diagnostic Test:** Ferric chloride test (turns deep blue/green) or silver nitrate test. * **Management:** Dietary restriction of phenylalanine and tyrosine; **Nitisinone** (inhibits 4-hydroxyphenylpyruvate dioxygenase) is used to reduce HGA production.

Question 436: Which one of the following is not a feature of Phenylketonuria?

A. Severe mental retardation
B. Reduced tendon reflexes (Correct Answer)
C. Enamel hypoplasia
D. Vomiting in early infancy

Explanation: **Phenylketonuria (PKU)** is an autosomal recessive disorder caused by a deficiency of the enzyme **phenylalanine hydroxylase (PAH)**, leading to the accumulation of phenylalanine and its metabolites (phenylketones). ### Explanation of Options: * **B. Reduced tendon reflexes (Correct Answer):** This is NOT a feature of PKU. In fact, patients with untreated PKU typically exhibit **hyperreflexia** (increased tendon reflexes) and spasticity. This occurs due to the toxic effects of phenylalanine on the developing central nervous system, leading to upper motor neuron signs rather than lower motor neuron signs. * **A. Severe mental retardation:** If left untreated, PKU leads to profound intellectual disability. High levels of phenylalanine interfere with amino acid transport across the blood-brain barrier and inhibit myelin formation. * **C. Enamel hypoplasia:** This is a documented clinical finding in children with PKU. The metabolic derangement during tooth development leads to defects in enamel formation. * **D. Vomiting in early infancy:** This is a common early clinical presentation. Infants often present with persistent vomiting, which can sometimes be misdiagnosed as pyloric stenosis. ### High-Yield Clinical Pearls for NEET-PG: * **Mousy/Musty Odor:** Due to the presence of **phenylacetic acid** in sweat and urine. * **Hypopigmentation:** Phenylalanine is a competitive inhibitor of tyrosinase. Reduced melanin synthesis leads to fair skin, blonde hair, and blue eyes. * **Diagnosis:** Screened via the **Guthrie Test** (bacterial inhibition assay). * **Management:** Dietary restriction of phenylalanine and supplementation of **Tyrosine** (which becomes an essential amino acid in these patients). * **Maternal PKU:** If a pregnant woman has high phenylalanine levels, the fetus may suffer from microcephaly, congenital heart defects, and mental retardation, even if the fetus is only a carrier.

Question 437: Classical type of galactosemia is due to deficiency of which enzyme?

A. galactokinase
B. aldose reductase
C. galactose-1-phosphate uridyltransferase (Correct Answer)
D. galactose dehydrogenase

Explanation: **Explanation:** Galactose metabolism follows the **Leloir pathway**. The question refers to **Classical Galactosemia**, which is an autosomal recessive disorder caused by a deficiency of **Galactose-1-phosphate uridyltransferase (GALT)**. 1. **Why Option C is Correct:** GALT is responsible for converting Galactose-1-phosphate and UDP-glucose into UDP-galactose and Glucose-1-phosphate. Its deficiency leads to the accumulation of **Galactose-1-phosphate** and **galactitol** in tissues (liver, brain, and renal tubules), causing severe organ damage. 2. **Why Other Options are Incorrect:** * **Galactokinase (Option A):** Deficiency causes "Non-classical Galactosemia." It is a milder condition characterized primarily by early-onset cataracts without the severe systemic involvement (liver/kidney failure) seen in the classical form. * **Aldose Reductase (Option B):** This enzyme reduces galactose to **galactitol** (dulcitol). It is not deficient; rather, its overactivity in the presence of high galactose levels leads to osmotic damage in the lens, causing cataracts. * **Galactose Dehydrogenase (Option D):** This is a minor alternative pathway enzyme and is not associated with the clinical syndrome of classical galactosemia. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Triad:** Hepatomegaly (jaundice/cirrhosis), infantile cataracts, and intellectual disability. * **Key Diagnostic Sign:** Reducing sugars in urine (Clinitest positive) but negative for glucose (Dipstick negative). * **Critical Complication:** Increased risk of **E. coli neonatal sepsis**. * **Management:** Immediate withdrawal of lactose/galactose from the diet (stop breastfeeding, switch to soy milk).

Question 438: All of the following are X-linked recessive disorders except?

A. Chronic granulomatous disease
B. Fragile X syndrome
C. Lesch-Nyhan syndrome
D. Ataxia telangiectasia (Correct Answer)

Explanation: **Explanation:** The correct answer is **Ataxia telangiectasia**, which is an **Autosomal Recessive (AR)** disorder. It is caused by a mutation in the *ATM* gene on chromosome 11, leading to defective DNA repair (specifically double-strand breaks). Clinically, it presents with the triad of cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency (IgA deficiency). **Analysis of Options:** * **Chronic Granulomatous Disease (CGD):** The most common form (approx. 70%) is **X-linked recessive**, caused by a mutation in the *CYBB* gene encoding the gp91phox subunit of NADPH oxidase. This leads to an inability of phagocytes to produce superoxide radicals, resulting in recurrent infections with catalase-positive organisms. * **Fragile X Syndrome:** This is an **X-linked dominant** disorder (with variable expressivity/reduced penetrance) often grouped under X-linked inheritance in competitive exams. It is caused by a CGG trinucleotide repeat expansion in the *FMR1* gene. * **Lesch-Nyhan Syndrome:** This is a classic **X-linked recessive** disorder caused by a deficiency of the enzyme **HGPRT** in the purine salvage pathway. It is characterized by hyperuricemia, gout, intellectual disability, and hallmark self-mutilating behavior. **High-Yield Clinical Pearls for NEET-PG:** * **Ataxia Telangiectasia:** Look for elevated **Alpha-fetoprotein (AFP)** levels in a child with gait instability; this is a highly specific diagnostic marker. * **X-linked Recessive Mnemonic:** "The **G**reedy **H**unter **L**oves **F**abry's **C**olorful **D**iamonds" (**G**6PD, **H**emophilia, **L**esch-Nyhan, **F**ragile X*, **C**GD, **D**uchenne MD). * **DNA Repair Defects:** Remember that Ataxia telangiectasia, Xeroderma pigmentosum, and Fanconi anemia are all **Autosomal Recessive**.

Question 439: Which of the following are characteristic features of Myophosphorylase deficiency?

A. McArdle's disease
B. Storage of glycogen in skeletal muscles
C. Muscle weakness and failure of exercise induced rise in blood lactate
D. All of the above (Correct Answer)

Explanation: **Explanation:** **Myophosphorylase deficiency**, also known as **McArdle’s Disease (Glycogen Storage Disease Type V)**, is an autosomal recessive disorder characterized by the inability to break down glycogen in skeletal muscles. 1. **Why Option D is correct:** * **McArdle’s Disease (Option A):** This is the clinical eponym for Type V GSD. The deficiency is strictly limited to the muscle isoform of glycogen phosphorylase. * **Glycogen Storage (Option B):** Since myophosphorylase is required to cleave glucose units from glycogen (glycogenolysis), its absence leads to the accumulation of structurally normal glycogen within skeletal muscle cells. * **Lactate Dynamics (Option C):** During exercise, muscles normally convert glucose to lactate via anaerobic glycolysis. In McArdle’s, the lack of glucose-1-phosphate (due to the block in glycogenolysis) means no substrate enters glycolysis. Consequently, there is a **failure of blood lactate to rise** following exercise—a classic diagnostic hallmark. 2. **Why other options are integrated:** Since all three statements (A, B, and C) accurately describe the pathophysiology and clinical presentation of the disease, "All of the above" is the correct choice. **High-Yield Clinical Pearls for NEET-PG:** * **Second Wind Phenomenon:** Patients experience improved exercise tolerance after a few minutes of activity as the body switches to using free fatty acids and blood glucose. * **Ischemic Forearm Exercise Test:** Classically shows a rise in ammonia but a **flat lactate curve**. * **Clinical Presentation:** Exercise-induced muscle cramps, fatigue, and **myoglobinuria** (burgundy-colored urine) after strenuous exertion due to rhabdomyolysis. * **Biochemical Note:** Unlike Von Gierke’s (Type I), there is **no hypoglycemia** because liver phosphorylase is normal.

Question 440: An infant is brought to a hospital because her wet diapers turn black when they are exposed to air. Physical examination is normal. Urine is positive both for reducing substance and when tested with ferric chloride. This disorder is caused by a deficiency of which of the following enzymes?

A. Homogentisic acid oxidase (Correct Answer)
B. Phenylalanine hydroxylase
C. L-histidine ammonialyase
D. Ketoacid decarboxylase

Explanation: **Explanation:** The clinical presentation of an infant whose diapers turn black upon exposure to air is the classic hallmark of **Alkaptonuria**. This autosomal recessive disorder is caused by a deficiency of **Homogentisic acid oxidase**, an enzyme in the phenylalanine and tyrosine catabolic pathway. **1. Why the Correct Answer is Right:** In Alkaptonuria, the deficiency of Homogentisic acid oxidase leads to the accumulation of **Homogentisic acid (HGA)**. When urine containing HGA is exposed to air, it undergoes oxidation and polymerization to form a brownish-black pigment called alkapton. HGA is a reducing agent, explaining the positive Benedict’s test (reducing substance), and it reacts with ferric chloride to produce a transient deep blue color. **2. Analysis of Incorrect Options:** * **B. Phenylalanine hydroxylase:** Deficiency causes **Phenylketonuria (PKU)**. Clinical features include intellectual disability, "mousy" body odor, and hypopigmentation, but not blackening of urine. * **C. L-histidine ammonialyase (Histidase):** Deficiency leads to **Histidinemia**. While it may show a positive ferric chloride test, it does not cause urine to darken. * **D. Ketoacid decarboxylase:** Deficiency of the Branched-chain alpha-keto acid dehydrogenase complex causes **Maple Syrup Urine Disease (MSUD)**, characterized by urine with a burnt-sugar odor and severe neurological distress. **Clinical Pearls for NEET-PG:** * **Ochronosis:** In adults, the pigment deposits in connective tissues (cartilage, sclera), leading to bluish-black discoloration. * **Arthritis:** Long-term accumulation leads to "Ochronotic arthritis," typically affecting large joints and the spine. * **Diagnosis:** Confirmed by detecting HGA in urine via Gas Chromatography-Mass Spectrometry (GC-MS). * **Dietary Management:** Restriction of Phenylalanine and Tyrosine; Nitisinone may be used to inhibit HGA production.

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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