Genetic Disorders and Biochemical Pathology — MCQs

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

Question 71: Find the type of inheritance?

A. Autosomal dominant
B. X-linked dominant
C. Autosomal recessive
D. Mitochondrial (Correct Answer)

Explanation: ***Mitochondrial*** - **Maternal inheritance** pattern where all offspring of an affected mother are affected, as mitochondria are inherited exclusively from the mother. - Shows **no paternal transmission** and affects both sexes equally without skipping generations through the maternal line. *Autosomal dominant* - Requires only **one copy** of the mutated gene to express the trait, with affected individuals in every generation. - Shows **vertical transmission** with approximately **50% risk** to each offspring, regardless of sex. *X-linked dominant* - Affects **more females than males** and shows transmission from affected fathers to **all daughters** but no sons. - Affected males cannot pass the trait to their sons, and affected females have a **50% risk** to each child. *Autosomal recessive* - Requires **two copies** of the mutated gene to express the trait, often showing **horizontal transmission** within generations. - Typically shows **consanguinity** in family history and affects both sexes equally with **25% risk** to siblings.

Question 72: Which enzyme defect causes phenylketonuria?

A. Phenylalanine oxidase
B. Phenylalanine hydroxylase (Correct Answer)
C. Tyrosinase
D. Tyrosine transaminase

Explanation: **Explanation:** **Phenylketonuria (PKU)** is an autosomal recessive metabolic disorder characterized by the body's inability to metabolize the essential amino acid phenylalanine. 1. **Why Phenylalanine Hydroxylase (PAH) is correct:** The primary defect in Classic PKU is a deficiency of the hepatic enzyme **Phenylalanine Hydroxylase**. This enzyme normally converts Phenylalanine into Tyrosine using **Tetrahydrobiopterin (BH4)** as a mandatory co-factor. When PAH is deficient, phenylalanine accumulates in the blood and tissues, while tyrosine becomes an "essential" amino acid for these patients. 2. **Why the other options are incorrect:** * **Phenylalanine oxidase:** This is not a standard enzyme in human phenylalanine metabolism; it is often used as a distractor in exams. * **Tyrosinase:** Deficiency of this enzyme leads to **Albinism**, as it is required for the conversion of Tyrosine to Melanin. * **Tyrosine transaminase:** Deficiency of this enzyme leads to **Tyrosinemia Type II** (Richner-Hanhart syndrome), characterized by palmoplantar keratosis and corneal ulcers. **High-Yield Clinical Pearls for NEET-PG:** * **Alternative Pathway:** When PAH is blocked, phenylalanine is diverted to form phenylketones (phenylpyruvate, phenyllactate, and phenylacetate), which give the urine a characteristic **"mousy" or "musty" odor**. * **Clinical Features:** Intellectual disability, microcephaly, and hypopigmentation (due to decreased melanin). * **Diagnosis:** Screened via the **Guthrie Test** (bacterial inhibition assay) or Tandem Mass Spectrometry. * **Management:** Dietary restriction of phenylalanine and supplementation of tyrosine. Avoid the sweetener **Aspartame**, as it contains phenylalanine. * **Maternal PKU:** High phenylalanine levels in a pregnant woman act as a teratogen, causing congenital heart defects and microcephaly in the fetus.

Question 73: Which enzyme deficiency leads to Pompe's disease?

A. Branching enzyme
B. Glucose-6-phosphatase
C. Acid maltase (Correct Answer)
D. Liver phosphorylase

Explanation: **Explanation:** **Pompe’s Disease (GSD Type II)** is unique among glycogen storage diseases because it is a **lysosomal storage disorder**. 1. **Why Acid Maltase is correct:** The enzyme **Acid α-1,4-glucosidase (Acid Maltase)** is responsible for breaking down glycogen within lysosomes. Its deficiency leads to the accumulation of glycogen in the lysosomes of nearly all tissues, most significantly in the heart, skeletal muscle, and liver. This results in massive cardiomegaly and progressive muscle weakness. 2. **Why other options are incorrect:** * **Branching enzyme (Option A):** Deficiency leads to **Andersen’s disease (GSD Type IV)**, characterized by long, unbranched glycogen chains (amylopectin-like) that trigger an immune response, leading to liver cirrhosis. * **Glucose-6-phosphatase (Option B):** Deficiency leads to **Von Gierke’s disease (GSD Type I)**, the most common GSD, presenting with severe fasting hypoglycemia, hepatomegaly, and hyperuricemia. * **Liver phosphorylase (Option D):** Deficiency leads to **Hers’ disease (GSD Type VI)**, a milder form of GSD presenting with hepatomegaly and growth retardation. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic:** "Pompe trashes the **Pump** (Heart)." * **Clinical Triad:** Cardiomegaly (massive), Hypotonia ("Floppy baby"), and early death due to heart failure. * **Key Distinction:** Unlike Von Gierke’s, there is **no hypoglycemia** in Pompe’s disease because cytoplasmic glycogenolysis remains intact. * **Diagnosis:** PAS-positive material in lysosomes; Enzyme assay in leukocytes or skin fibroblasts. * **Treatment:** Enzyme Replacement Therapy (Alglucosidase alfa).

Question 74: Enzyme replacement therapy is available for which of the following conditions?

A. Gaucher's disease (Correct Answer)
B. Galactosemia
C. Fructosuria
D. None of the above

Explanation: **Explanation:** **Gaucher’s disease** is the correct answer because it is a classic Lysosomal Storage Disorder (LSD) caused by a deficiency of the enzyme **Glucocerebrosidase** (Acid $\beta$-glucosidase). Enzyme Replacement Therapy (ERT) is the gold standard treatment for Type 1 Gaucher’s disease. Recombinant enzymes such as **Imiglucerase**, Velaglucerase alfa, and Taliglucerase are administered intravenously to break down the accumulated glucocerebroside in macrophages (Gaucher cells). **Why other options are incorrect:** * **Galactosemia:** This is an inborn error of carbohydrate metabolism (most commonly GALT deficiency). Management relies strictly on **dietary modification** (elimination of lactose and galactose) rather than ERT, as the enzyme cannot effectively reach the intracellular sites of action in the liver and brain. * **Fructosuria:** Essential fructosuria (Fructokinase deficiency) is a **benign, asymptomatic condition** where fructose is excreted in the urine. It requires no treatment or ERT. **High-Yield Clinical Pearls for NEET-PG:** * **Gaucher’s Disease:** Look for the triad of **hepatosplenomegaly, bone pain (Erlenmeyer flask deformity), and pancytopenia.** Histology shows "crinkled paper" cytoplasm in macrophages. * **Other LSDs with ERT:** ERT is also available for **Fabry’s disease** (Agalsidase beta), **Pompe’s disease** (Alglucosidase alfa), and **MPS I (Hurler syndrome)** (Laronidase). * **Tay-Sachs Disease:** Notably, ERT is **not** effective for Tay-Sachs because the enzyme cannot cross the blood-brain barrier to treat the primary neurological symptoms.

Question 75: Which of the following is FALSE regarding hereditary fructose intolerance?

A. Deficiency of fructose 1-phosphate aldolase.
B. Accumulation of fructose 1-phosphate in tissues.
C. Hyperglycemia. (Correct Answer)
D. Liver and kidneys are involved.

Explanation: **Explanation:** Hereditary Fructose Intolerance (HFI) is an autosomal recessive disorder caused by a deficiency of **Aldolase B** (Fructose 1-phosphate aldolase). **Why Option C is the correct (False) statement:** HFI is characterized by **severe hypoglycemia**, not hyperglycemia. The deficiency leads to the intracellular accumulation of **Fructose 1-phosphate (F1P)**. This "trapping" of inorganic phosphate depletes the cellular ATP and Pi pools. Low Pi levels inhibit **Glycogen Phosphorylase**, preventing glycogenolysis, while the lack of ATP and high F1P levels inhibit **Gluconeogenesis**. The inability to perform these two processes results in profound postprandial hypoglycemia following fructose ingestion. **Analysis of other options:** * **Option A:** Correct. Aldolase B is the specific enzyme deficient in HFI. * **Option B:** Correct. Without Aldolase B, Fructose 1-phosphate cannot be cleaved into DHAP and Glyceraldehyde, leading to its accumulation in hepatocytes, enterocytes, and proximal tubule cells. * **Option D:** Correct. Aldolase B is primarily expressed in the **liver, kidney, and small intestine**. Consequently, HFI manifests with hepatic failure (jaundice, cirrhosis) and renal tubular dysfunction (Fanconi-like syndrome). **NEET-PG High-Yield Pearls:** * **Clinical Presentation:** Symptoms appear when an infant is weaned from breast milk and introduced to fruits/sucrose (fructose + glucose). * **Key Finding:** Reducing sugars in urine (Clinitest positive) but negative glucose oxidase test (Dipstick). * **Management:** Strict removal of fructose, sucrose, and sorbitol from the diet. * **Contrast:** Essential Fructosuria (Fructokinase deficiency) is a benign, asymptomatic condition.

Question 76: Cirrhosis can be seen in all of the following metabolic diseases EXCEPT?

A. Tyrosinemia
B. Galactosemia
C. McArdle disease (Correct Answer)
D. Hereditary fructose intolerance

Explanation: **Explanation:** The correct answer is **McArdle disease (Option C)**. This is because McArdle disease (Glycogen Storage Disease Type V) is a **purely muscular disorder**. It is caused by a deficiency of **muscle glycogen phosphorylase (myophosphorylase)**. Since the enzyme defect is localized strictly to skeletal muscle, the liver is unaffected, and there is no risk of cirrhosis or hepatic dysfunction. Clinical features are limited to exercise intolerance, muscle cramps, and myoglobinuria. **Why the other options are incorrect:** * **Tyrosinemia (Type I):** Caused by a deficiency of fumarylacetoacetate hydrolase. The accumulation of toxic metabolites (like succinylacetone) leads to severe progressive liver damage, early-onset cirrhosis, and a high risk of hepatocellular carcinoma. * **Galactosemia:** Deficiency of Galactose-1-phosphate uridyltransferase (GALT) leads to the accumulation of Galactose-1-phosphate in the liver. This is hepatotoxic and results in neonatal jaundice, hepatomegaly, and eventually cirrhosis if lactose is not removed from the diet. * **Hereditary Fructose Intolerance (HFI):** Deficiency of Aldolase B leads to the trapping of Fructose-1-phosphate in hepatocytes. This depletes intracellular ATP and inorganic phosphate, causing hepatic dysfunction, jaundice, and cirrhosis upon ingestion of fructose or sucrose. **NEET-PG High-Yield Pearls:** * **GSDs with Liver Involvement:** Type I (von Gierke), Type III (Cori), and Type IV (Andersen) involve the liver. **Type IV** is particularly known for causing early, progressive cirrhosis. * **GSDs with Muscle Involvement:** Type V (McArdle) and Type VII (Tarui). * **Key Diagnostic:** In McArdle disease, the **Ischemic Forearm Exercise Test** shows a failure of blood lactate to rise, which is a classic exam favorite.

Question 77: Which of the following statements about mitochondrial disorders is FALSE?

A. May present at any age and by mode of inheritance
B. Include Pearson's syndrome
C. Features may include retinitis pigmentosa
D. Elevated free-floating blood lactate does not support the diagnosis (Correct Answer)

Explanation: **Explanation:** **1. Why Option D is the Correct (False) Statement:** Mitochondria are the primary site of aerobic respiration and the Citric Acid (TCA) cycle. When mitochondrial function is impaired, cells cannot efficiently oxidize pyruvate. This leads to a shift toward anaerobic metabolism, where pyruvate is converted into lactate by lactate dehydrogenase. Consequently, **elevated serum lactate (lactic acidosis)** and an increased lactate-to-pyruvate ratio are hallmark biochemical markers that **strongly support** the diagnosis of mitochondrial disorders. **2. Analysis of Other Options:** * **Option A:** Mitochondrial disorders can present at any age (from neonatal to late adulthood). While classic mitochondrial DNA (mtDNA) is inherited **maternally**, many mitochondrial proteins are encoded by **nuclear DNA (nDNA)**, which can follow Autosomal Dominant, Autosomal Recessive, or X-linked inheritance patterns. * **Option B:** **Pearson’s Syndrome** is a classic mitochondrial disorder caused by large-scale mtDNA deletions, characterized by sideroblastic anemia and exocrine pancreatic insufficiency. * **Option C:** **Retinitis pigmentosa** (pigmentary retinopathy) is a frequent clinical feature in several mitochondrial syndromes, most notably **NARP** (Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa) and **Kearns-Sayre Syndrome**. **Clinical Pearls for NEET-PG:** * **Heteroplasmy:** The coexistence of mutated and wild-type mtDNA in a single cell; the ratio determines the clinical severity (Threshold effect). * **Maternal Inheritance:** Only females pass on mtDNA mutations to all offspring; males do not pass them on. * **Common Syndromes:** * **MELAS:** Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes. * **MERRF:** Myoclonic Epilepsy with Ragged Red Fibers (seen on Gomori trichrome stain). * **LHON:** Leber’s Hereditary Optic Neuropathy (painless subacute vision loss).

Question 78: McArdle disease is caused by a deficiency in the metabolism of which particular compound?

A. Glycogen (Correct Answer)
B. Collagen
C. Dopamine
D. Valine

Explanation: **McArdle Disease (GSD Type V)** is a metabolic disorder caused by a deficiency of the enzyme **muscle phosphorylase** (myophosphorylase). This enzyme is responsible for the rate-limiting step in glycogenolysis—the breakdown of **glycogen** into glucose-1-phosphate in muscle tissue. Without it, muscles cannot mobilize glucose during strenuous exercise, leading to energy failure. ### Why the correct answer is right: * **Glycogen:** In McArdle disease, glycogen cannot be broken down in skeletal muscles. This leads to an accumulation of normal-structured glycogen within the muscle cells. Patients typically present with exercise intolerance, muscle cramps, and "second wind" phenomenon. ### Why the incorrect options are wrong: * **Collagen:** Defects in collagen synthesis or structure lead to disorders like **Ehlers-Danlos Syndrome** or **Osteogenesis Imperfecta**, not metabolic storage diseases. * **Dopamine:** Deficiency of dopamine in the nigrostriatal pathway is the hallmark of **Parkinson’s Disease**. * **Valine:** This is a branched-chain amino acid. Defects in its metabolism (along with leucine and isoleucine) lead to **Maple Syrup Urine Disease (MSUD)**. ### High-Yield Clinical Pearls for NEET-PG: * **Ischemic Forearm Exercise Test:** A classic diagnostic test where the patient shows a **failure of blood lactate to rise** after exercise (since glycogen cannot be converted to lactate). * **Myoglobinuria:** Intense exercise can cause rhabdomyolysis, leading to "burgundy-colored" urine and potential acute renal failure. * **Second Wind Phenomenon:** Patients experience improved exercise tolerance after 10–15 minutes once the body switches to using fatty acids and blood glucose as fuel. * **Enzyme Mnemonic:** **M**cArdle = **M**uscle phosphorylase deficiency.

Question 79: Which of the following conditions does not involve the skin?

A. Erythropoietic porphyria
B. Porphyria cutanea tarda
C. Acute intermittent porphyria (Correct Answer)
D. Hereditary coproporphyria

Explanation: **Explanation:** The porphyrias are a group of metabolic disorders caused by deficiencies in the enzymes of the heme biosynthetic pathway. The clinical presentation depends on whether the metabolic block occurs early or late in the pathway. **Why Option C is correct:** **Acute Intermittent Porphyria (AIP)** is caused by a deficiency of **Porphobilinogen (PBG) deaminase**. This results in the accumulation of early precursors, **ALA (Aminolevulinic acid) and PBG**. These precursors are neurotoxic but not photosensitive. Therefore, AIP presents with the "5 Ps": Abdominal **P**ain, **P**olyneuropathy, **P**sychological disturbances, **P**ink urine, and **P**recipitated by drugs (e.g., Barbiturates). It is the most common acute porphyria and characteristically **lacks any skin involvement.** **Why the other options are incorrect:** * **A. Erythropoietic Porphyria (CEP):** Also known as Günther disease, it involves a deficiency of Uroporphyrinogen III synthase. It presents with extreme cutaneous photosensitivity, blistering, and scarring. * **B. Porphyria Cutanea Tarda (PCT):** The most common porphyria overall. Due to Uroporphyrinogen decarboxylase deficiency, it leads to the accumulation of porphyrins in the skin, causing chronic blistering on sun-exposed areas. * **D. Hereditary Coproporphyria (HCP):** This is a "mixed" porphyria. Because the block occurs later in the pathway (Coproporphyrinogen oxidase), it can present with both acute neurological attacks and cutaneous photosensitivity. **High-Yield NEET-PG Pearls:** 1. **Rule of Thumb:** If the enzyme deficiency occurs **before** the formation of tetrapyrroles (like in AIP), the symptoms are **Neurological**. If the deficiency occurs **after** the formation of tetrapyrroles (like in PCT or CEP), the symptoms are **Cutaneous** (Photosensitivity). 2. **Urine Finding:** In AIP, urine is colorless when fresh but turns **"Port-wine" red** upon standing/exposure to light due to the oxidation of PBG to porphobilin. 3. **Enzyme Mnemonic:** AIP = **A**lmost **I**nvisible **P**orphyrins (No skin signs).

Question 80: An infant presents with hepatosplenomegaly, hypoglycemia, hyperuricemia, and lactic acidosis. Liver biopsy shows normal structured glycogen deposition. Which enzyme is deficient in this infant?

A. Debranching enzyme
B. Branching enzyme
C. Glucose-6-phosphatase (Correct Answer)
D. Muscle phosphorylase

Explanation: **Explanation:** The clinical presentation of hepatosplenomegaly, fasting hypoglycemia, hyperuricemia, and lactic acidosis is the classic "tetrad" of **Von Gierke Disease (Glycogen Storage Disease Type I)**. **1. Why Glucose-6-phosphatase is correct:** Glucose-6-phosphatase is the final enzyme in both glycogenolysis and gluconeogenesis, responsible for converting Glucose-6-Phosphate into free glucose. * **Hypoglycemia:** Inability to release free glucose into the blood. * **Lactic Acidosis:** Excess G6P is shunted into the glycolytic pathway, increasing lactate. * **Hyperuricemia:** Increased G6P enters the Pentose Phosphate Pathway, leading to increased purine synthesis and degradation to uric acid. * **Normal Glycogen Structure:** Unlike debranching or branching enzyme defects, the glycogen itself is synthesized normally but cannot be mobilized, leading to massive accumulation in the liver. **2. Why the other options are incorrect:** * **Debranching enzyme (Type III - Cori Disease):** Presents with hepatomegaly and hypoglycemia, but **lactic acid levels are normal**, and the glycogen has an abnormal structure (short outer chains/limit dextrins). * **Branching enzyme (Type IV - Andersen Disease):** Characterized by "amylopectin-like" abnormal glycogen structure and early-onset liver cirrhosis/failure. Hypoglycemia is a late finding. * **Muscle phosphorylase (Type V - McArdle Disease):** Affects skeletal muscle only. Presents with exercise-induced cramps and myoglobinuria; it does not cause hepatomegaly or hypoglycemia. **High-Yield Clinical Pearls for NEET-PG:** * **GSD Type Ia:** Deficiency of Glucose-6-phosphatase. * **GSD Type Ib:** Deficiency of Glucose-6-phosphate translocase (presents with additional **neutropenia** and recurrent infections). * **Key Lab Finding:** Hyperlipidemia (doll-like facies due to fat deposition) is also common in Type I. * **Treatment:** Frequent oral glucose/cornstarch and avoidance of fructose/galactose.

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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