Inborn Errors of Metabolism — MCQs

10 questions

Which one of the following disorders does not depend on pyridoxine for treatment?

Tay-Sachs disease is due to a deficiency of which enzyme?

An 8-month-old infant is brought in with poor feeding, lethargy, hypotonia, and hepatomegaly. Labs reveal hypoglycemia and metabolic acidosis. Which condition is most likely?

A 5 year old child was brought to the physician with a history of black urine. There is no history of fever or any other complaints. There is no growth retardation and all the developmental milestones are normal. The child is suspected to have an enzyme defect for metabolism of an aromatic amino acid. What is the enzyme deficient

In alkaptonuria, deficiency is:

In Zellweger syndrome, which of the following is absent?

Increased uric acid levels are seen in which glycogen storage disease ?

Which of the following statements regarding phenylketonuria (PKU) is false?

Increasing severity of intellectual disability of male members over generations is a result of ?

Q10

Which of the following statements is NOT true about medium chain acyl-CoA dehydrogenase deficiency?

Inborn Errors of Metabolism Indian Medical PG Practice Questions and MCQs

Question 1: Which one of the following disorders does not depend on pyridoxine for treatment?

A. Homocystinuria
B. Cystathioninuria
C. Xanthurenic aciduria
D. Methylmalonic acidemia (Correct Answer)

Explanation: ***Methylmalonic acidemia*** - This condition is caused by a deficiency in the enzyme **methylmalonyl CoA mutase** or its coenzyme, **adenosylcobalamin (a derivative of vitamin B12)**. - Therefore, treatment primarily involves dietary management and supplementation with **vitamin B12**, not pyridoxine (vitamin B6). *Homocystinuria* - Many forms of homocystinuria, particularly those involving a deficiency in **cystathionine beta-synthase**, respond to large doses of **pyridoxine (vitamin B6)**. - Pyridoxine acts as a coenzyme for cystathionine beta-synthase, helping to reduce **homocysteine** levels. *Cystathioninuria* - This metabolic disorder results from a deficiency in **cystathionine gamma-lyase**, an enzyme that requires **pyridoxal phosphate (active form of vitamin B6)** as a coenzyme. - Supplementation with **pyridoxine** can normalize or reduce the excretion of cystathionine in the urine for many affected individuals. *Xanthurenic aciduria* - This condition is often associated with a deficiency in **kynureninase**, an enzyme in the **tryptophan metabolism pathway** that requires **pyridoxal phosphate** as a coenzyme. - Supplementation with **pyridoxine** can typically correct the metabolic defect and normalize xanthurenic acid excretion.

Question 2: Tay-Sachs disease is due to a deficiency of which enzyme?

A. Hexosaminidase B
B. α-galactosidase
C. Hexosaminidase A (Correct Answer)
D. Sphingomyelinase

Explanation: ***Hexosaminidase A*** - **Tay-Sachs disease** is caused by a genetic deficiency in the lysosomal enzyme **hexosaminidase A (HexA)**. - This deficiency leads to the accumulation of **GM2 ganglioside** in neuronal cells, particularly in the brain, causing progressive neurodegeneration. *Hexosaminidase B* - A deficiency in **hexosaminidase B** is associated with **Sandhoff disease**, a lysosomal storage disorder similar to Tay-Sachs but typically more severe. - While HexA is composed of alpha and beta subunits, a deficiency specifically in the beta subunit is characteristic of Sandhoff disease. *α-galactosidase* - A deficiency in **α-galactosidase** is responsible for **Fabry disease**, an X-linked lysosomal storage disorder. - It leads to the accumulation of **globotriaosylceramide (Gb3)**, primarily affecting the kidneys, heart, and nervous system, and does not present with the neurological symptoms of Tay-Sachs. *Sphingomyelinase* - A deficiency in **sphingomyelinase** causes **Niemann-Pick disease (Type A and B)**, another lysosomal storage disorder. - This leads to the accumulation of **sphingomyelin** in various organs, resulting in hepatosplenomegaly, neurodegeneration (in Type A), and lung disease, distinct from Tay-Sachs.

Question 3: An 8-month-old infant is brought in with poor feeding, lethargy, hypotonia, and hepatomegaly. Labs reveal hypoglycemia and metabolic acidosis. Which condition is most likely?

A. Hereditary fructose intolerance
B. Galactosemia
C. Pompe disease
D. Von Gierke disease (Correct Answer)
E. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

Explanation: ***Von Gierke disease*** - **Type I glycogen storage disease** (GSD I) typically presents in infancy with **hypoglycemia** (due to impaired glucose release from glycogen), **hepatomegaly** (due to glycogen accumulation), and **lactic acidosis**. - Other common findings include **hyperlipidemia** and **hyperuricemia**, while **hypotonia** and **poor feeding** are generalized symptoms stemming from metabolic derangements. *Hereditary fructose intolerance* - This condition presents when **fructose** is introduced into the diet, typically after 4-6 months of age, with symptoms like **nausea, vomiting, abdominal pain**, and **hepatomegaly**. - While it can cause **hypoglycemia** and **metabolic acidosis**, the profound **hypotonia** and general metabolic collapse described in an 8-month-old on a typical diet makes GSD I more likely initially. *Galactosemia* - Symptoms usually appear within days or weeks of birth upon the initiation of **milk feeding**, including **vomiting, lethargy, poor feeding, jaundice, hepatomegaly**, and **cataracts**. - While it causes **hypoglycemia** and can lead to acidosis and hypotonia, the age of presentation and lack of specific mention of jaundice or cataracts makes it a less precise fit. *Pompe disease* - Also known as **glycogen storage disease type II**, it is characterized by the accumulation of glycogen in **lysosomes**, primarily affecting muscles. - The infantile form presents with severe **cardiomyopathy**, **muscle weakness**, and **hypotonia**, but **hypoglycemia** and **hepatomegaly** are not its primary or most prominent features. *Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency* - A **fatty acid oxidation disorder** that presents with episodic **hypoglycemia** (particularly during fasting or illness), **lethargy**, and **hepatomegaly**. - Key distinguishing features include **hypoketotic hypoglycemia** and elevated **dicarboxylic acids** on urine organic acids, but the **lactic acidosis** and overall metabolic profile are more consistent with GSD I.

Question 4: A 5 year old child was brought to the physician with a history of black urine. There is no history of fever or any other complaints. There is no growth retardation and all the developmental milestones are normal. The child is suspected to have an enzyme defect for metabolism of an aromatic amino acid. What is the enzyme deficient

A. Homogentisate dehydrogenase
B. Homogentistae oxidase (Correct Answer)
C. Tyrosine Transaminase
D. Tryptophan Hydroxylase
E. Phenylalanine Hydroxylase

Explanation: ***Homogentistae oxidase*** - The presentation of a child with **black urine** (alkaptonuria) in the absence of other symptoms is characteristic of a deficiency in **homogentisate oxidase**. - This enzyme is crucial in the catabolism of **tyrosine**, and its deficiency leads to the accumulation of **homogentisic acid**, which oxidizes upon exposure to air, turning urine black. *Homogentisate dehydrogenase* - This enzyme is not a recognized component of the **tyrosine degradation pathway** in humans. - The correct enzyme involved in the breakdown of **homogentisate** is an oxidase, not a dehydrogenase, in this context. *Tyrosine Transaminase* - A deficiency in **tyrosine transaminase** (tyrosinemia type II) would lead to elevated tyrosine levels and typically presents with symptoms affecting the eyes, skin, and intellectual disability, not primarily black urine. - This condition is characterized by **ocular findings** (corneal ulcers), **skin lesions**, and **neurological symptoms**. *Tryptophan Hydroxylase* - This enzyme is involved in the synthesis of **serotonin** and **melatonin** from tryptophan, a different amino acid pathway. - A deficiency or abnormality in **tryptophan hydroxylase** would not cause black urine but could lead to neurological or mood disorders. *Phenylalanine Hydroxylase* - A deficiency in **phenylalanine hydroxylase** causes **phenylketonuria (PKU)**, which affects phenylalanine metabolism, not tyrosine metabolism directly. - PKU typically presents with **intellectual disability**, **musty odor**, **fair skin**, and **seizures** if untreated, not black urine.

Question 5: In alkaptonuria, deficiency is:

A. Phosphofructokinase
B. HMG CoA reductase
C. Homogentisate oxidase (Correct Answer)
D. Xanthine oxidase

Explanation: ***Homogentisate oxidase*** - **Alkaptonuria** is an autosomal recessive disorder caused by a deficiency of the enzyme **homogentisate 1,2-dioxygenase** (also known as homogentisate oxidase). - This enzyme is crucial in the **catabolic pathway of tyrosine**, specifically breaking down **homogentisic acid**. *Phosphofructokinase* - Deficiency of **phosphofructokinase** (PFK) causes **Tarui's disease** (Glycogen Storage Disease Type VII), affecting **glycolysis**. - Symptoms include exercise intolerance, muscle pain, and hemolysis, which are unrelated to alkaptonuria. *HMG CoA reductase* - **HMG-CoA reductase** is the rate-limiting enzyme in **cholesterol biosynthesis**, and its inhibitors (statins) are used to lower cholesterol levels. - Its deficiency is not associated with alkaptonuria. *Xanthine oxidase* - **Xanthine oxidase** is involved in the catabolism of **purines**, converting hypoxanthine to xanthine and then xanthine to uric acid. - Its deficiency causes **xanthinuria**, leading to kidney stones, and it is not associated with alkaptonuria.

Question 6: In Zellweger syndrome, which of the following is absent?

A. Golgi apparatus
B. Peroxisomes (Correct Answer)
C. Mitochondria
D. ER

Explanation: ***Peroxisomes*** - **Zellweger syndrome** is an **autosomal recessive disorder** characterized by a severe reduction or absence of functional peroxisomes. - Peroxisomes are essential organelles involved in **lipid metabolism**, particularly the breakdown of very long-chain fatty acids (VLCFAs) and branched-chain fatty acids, leading to their accumulation in the blood and tissues. *Golgi apparatus* - The **Golgi apparatus** is an intact and functional organelle in Zellweger syndrome. - It plays a crucial role in modifying, sorting, and packaging proteins and lipids for secretion or delivery to other organelles, functions that remain unaffected in this condition. *Mitochondria* - **Mitochondria**, responsible for cellular respiration and ATP production, are present and functional in Zellweger syndrome. - While metabolic disturbances occur, they are not due to primary mitochondrial dysfunction. *ER* - The **endoplasmic reticulum (ER)**, a network of membranes involved in protein and lipid synthesis, is also intact and functional. - It is not directly implicated in the pathogenesis of Zellweger syndrome.

Question 7: Increased uric acid levels are seen in which glycogen storage disease ?

A. Type I (Von Gierke's disease) (Correct Answer)
B. Type II (Pompe disease)
C. Type IV (Andersen disease)
D. Type III (Cori disease)

Explanation: ***Type I (Von Gierke's disease)*** - In **Von Gierke's disease**, the deficiency of **glucose-6-phosphatase** leads to accumulation of glucose-6-phosphate in hepatocytes. - **Hyperuricemia** occurs due to: 1. **Increased purine degradation** - Metabolic stress leads to accelerated ATP breakdown and increased uric acid production 2. **Decreased renal excretion** - Lactic acidosis (from G6P → pyruvate → lactate) competitively inhibits uric acid secretion in renal tubules 3. **Enhanced purine synthesis** - Increased availability of ribose-5-phosphate from pentose phosphate pathway - Classic triad: **Hepatomegaly, hypoglycemia, and lactic acidosis with hyperuricemia** *Type II (Pompe disease)* - Caused by a deficiency of **acid alpha-glucosidase** (acid maltase), leading to glycogen accumulation in **lysosomes**. - Primarily affects the **heart**, **muscles**, and **liver**, but does not cause hyperuricemia. *Type IV (Andersen disease)* - Results from a deficiency of **glycogen branching enzyme**, leading to the formation of abnormal glycogen with long, unbranched chains. - Primarily affects the **liver** and **spleen**, causing cirrhosis and hepatic failure, but not hyperuricemia. *Type III (Cori disease)* - Caused by a deficiency of **glycogen debranching enzyme** (amylo-1,6-glucosidase), leading to abnormal accumulation of glycogen with short outer branches. - Presents with hepatomegaly, hypoglycemia, and muscle weakness, but **hyperuricemia is not a characteristic feature**.

Question 8: Which of the following statements regarding phenylketonuria (PKU) is false?

A. Blood phenyl alanine level >20 mg/dl causes severe disease
B. Neurological symptoms are due to deficiency of phenylalanine hydroxylase. (Correct Answer)
C. Method of choice for screening is blood phenylalanine by Guthrie's test.
D. PKU is caused by a deficiency of phenylalanine hydroxylase.

Explanation: ***Neurological symptoms are due to deficiency of phenylalanine hydroxylase.*** - This statement is **FALSE** - it confuses the cause with the mechanism. - Neurological symptoms in PKU are caused by the **accumulation of phenylalanine and its toxic metabolites** (such as phenylpyruvate, phenyllactate, and phenylacetate) in the brain, not directly by the enzyme deficiency itself. - The deficiency of **phenylalanine hydroxylase** is the underlying cause, but the **toxic buildup** is what damages the developing brain, leading to intellectual disability, seizures, and behavioral problems. *Blood phenyl alanine level >20 mg/dl causes severe disease* - This statement is **TRUE**. - Blood phenylalanine levels **>20 mg/dL** are diagnostic of **classical PKU**, which causes severe disease if untreated. - Normal phenylalanine levels are 1-2 mg/dL; levels >20 mg/dL require strict dietary management to prevent neurological damage. *Method of choice for screening is blood phenylalanine by Guthrie's test.* - This statement is **TRUE** in the traditional context taught for medical exams. - The **Guthrie bacterial inhibition assay** measures blood phenylalanine from a heel prick and has been the standard newborn screening method for decades. - While modern laboratories increasingly use **tandem mass spectrometry (MS/MS)**, the Guthrie test remains a validated and widely taught screening method. *PKU is caused by a deficiency of phenylalanine hydroxylase.* - This statement is **TRUE**. - **Phenylketonuria (PKU)** is an autosomal recessive disorder caused by mutations in the **PAH gene**, leading to deficiency of the enzyme **phenylalanine hydroxylase**. - This enzyme normally converts phenylalanine to tyrosine; its absence leads to phenylalanine accumulation.

Question 9: Increasing severity of intellectual disability of male members over generations is a result of ?

A. Y linked disorder
B. Frameshift mutation
C. Trinucleotide repeat mutation (Correct Answer)
D. Mitochondrial DNA mutation

Explanation: ***Trinucleotide repeat mutation*** - This phenomenon, known as **anticipation**, is characteristic of disorders caused by trinucleotide repeat expansions like **Fragile X syndrome**, where the number of repeats increases in successive generations, leading to earlier onset and more severe symptoms. - The expansion of these repeats often occurs during **meiosis**, particularly **oogenesis** for Fragile X, contributing to the increasing severity observed in offspring. *Y linked disorder* - Y-linked disorders affect only males and are passed from father to son, but they do not typically show increasing severity over generations or the phenomenon of anticipation. - Their inheritance pattern is straightforward and generally consistent across generations, without progressive phenotypic changes. *Frameshift mutation* - A **frameshift mutation** involves the insertion or deletion of nucleotides that are not multiples of three, leading to a shift in the reading frame and an altered protein sequence. - While they can cause severe genetic disorders, **frameshift mutations** do not typically explain the observed increase in severity across generations (anticipation). *Mitochondrial DNA mutation* - Mitochondria are inherited exclusively from the mother, and mutations in **mitochondrial DNA** can cause a range of disorders affecting energy production. - While these disorders can vary in severity due to **heteroplasmy**, they do not typically show a pattern of increasing severity in successive generations due to an expanding repeat sequence.

Question 10: Which of the following statements is NOT true about medium chain acyl-CoA dehydrogenase deficiency?

A. Autosomal recessive inheritance
B. Cardiomyopathy (Correct Answer)
C. Hypoketotic hypoglycemia
D. Episodes associated with fasting

Explanation: ***Cardiomyopathy*** - While other fatty acid oxidation disorders can present with **cardiomyopathy**, Medium Acyl-CoA Dehydrogenase Deficiency (MCADD) primarily affects the **liver** and **skeletal muscle**, not the heart. - The classic presentation involves episodes of **hypoketotic hypoglycemia** and **lethargy**, often triggered by fasting or illness. *Autosomal recessive inheritance* - MCADD is indeed inherited in an **autosomal recessive pattern**, meaning an individual must inherit two copies of the mutated gene (one from each parent) to be affected. - This is a characteristic feature of many **inborn errors of metabolism**, including fatty acid oxidation disorders. *Hypoketotic hypoglycemia* - This is a hallmark feature of MCADD, as the body cannot effectively break down **medium-chain fatty acids** into ketones for energy during periods of fasting. - The buildup of toxic intermediates and lack of ketosis contribute to the acute metabolic crises observed in affected individuals. *Episodes associated with fasting* - Fasting is a common trigger for metabolic decompensation in MCADD, as the body becomes reliant on **fatty acid oxidation** for energy when glucose stores are depleted. - Illnesses that reduce appetite or increase energy demands, leading to prolonged fasting, can precipitate acute crises.

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