Mucopolysaccharidoses — MCQs

10 questions

A 5-month-old boy is brought to his pediatrician because his parents have noticed that he has very restricted joint movement. He was born at home without prenatal care, but they say that he appeared healthy at birth. Since then, they say that he doesn't seem to move very much and is hard to arouse. Physical exam reveals coarse facial structures and hepatosplenomegaly. Radiography reveals skeletal malformations, and serum tests show high plasma levels of lysosomal enzymes. The production of which of the following substances will most likely be disrupted in this patient?

An 18-month-old girl is brought to the pediatrician’s office for failure to thrive and developmental delay. The patient’s mother says she has not started speaking and is just now starting to pull herself up to standing position. Furthermore, her movement appears to be restricted. Physical examination reveals coarse facial features and restricted joint mobility. Laboratory studies show increased plasma levels of several enzymes. Which of the following is the underlying biochemical defect in this patient?

An 18-month-old boy is brought in by his parents for a routine check-up. The parents state that the patient still has not had any language development, and they are concerned about developmental delay. Of note, they have also noticed that the patient’s facial features have changed significantly in the last year. The patient also seems to have trouble visually focusing on objects or on the television. On exam, the patient's temperature is 98.2°F (36.8°C), blood pressure is 108/72 mmHg, pulse is 86/min, and respirations are 14/min. Of interest, the patient has not increased much in length or weight in the past 3 months. He is now in the 25th percentile for weight but is in the 90th percentile for head circumference. The patient does not appear to have any gross or fine motor deficiencies. Of note, he has coarse facial features that were not previously noted, including a long face, prominent forehead, and protruding eyes. The patient has corneal clouding bilaterally. At rest, the patient keeps his mouth hanging open. After extensive workup, the patient is found to have 2 mutated copies of the IDUA gene, with no production of the protein iduronidase. Which of the following is the likely mutation found in this disease?

A 4-week-old infant is brought to the physician by his mother because of blood-tinged stools for 3 days. He has also been passing whitish mucoid strings with the stools during this period. He was delivered at 38 weeks' gestation by lower segment transverse cesarean section because of a nonreassuring fetal heart rate. He was monitored in the intensive care unit for a day prior to being discharged. His 6-year-old brother was treated for viral gastroenteritis one week ago. The patient is exclusively breastfed. He is at the 50th percentile for height and 60th percentile for weight. He appears healthy and active. His vital signs are within normal limits. Examination shows a soft and nontender abdomen. The liver is palpated just below the right costal margin. The remainder of the examination shows no abnormalities. Test of the stool for occult blood is positive. A complete blood count and serum concentrations of electrolytes and creatinine are within the reference range. Which of the following is the most appropriate next step in management?

A 4-month-old boy is brought to the emergency department by his mother because of lethargy and vomiting since he woke up 1 hour ago. The mother says that he last breastfed the previous evening and slept through the night for the first time. His family recently immigrated from Bolivia. His temperature is 38.7°C (101.2°F). Physical examination shows dry mucous membranes and enlarged, reddened tonsils. Serum studies show: Glucose 42 mg/dL Ketones 0.2 mg/dL N = < 1 mg/dL AST 40 U/L ALT 60 U/L Ammonia 80 μ/dL (N=15–45) Which of the following enzymes is most likely deficient in this patient?

A deficiency in which of the following lysosomal enzymes is inherited in a pattern similar to a deficiency of iduronate sulfatase (Hunter syndrome)?

A 6-month-old boy is referred to a geneticist after he is found to have persistent hypotonia and failure to thrive. He has also had episodes of what appears to be respiratory distress and has an enlarged heart on physical exam. There is a family history of childhood onset hypertrophic cardiomyopathy, so a biopsy is performed showing electron dense granules within the lysosomes. Genetic testing is performed showing a defect in glycogen processing. A deficiency in which of the following enzymes is most likely to be responsible for this patient's symptoms?

A 9-month-old girl is brought to the physician because of a 1-month history of poor feeding and irritability. She is at the 15th percentile for height and 5th percentile for weight. Examination shows hypotonia and wasting of skeletal muscles. Cardiopulmonary examination shows no abnormalities. There is hepatomegaly. Her serum glucose is 61 mg/dL, creatinine kinase is 100 U/L, and lactic acid is within the reference range. Urine ketone bodies are elevated. Which of the following enzymes is most likely deficient in this patient?

A 3-month-old African American infant presents to the hospital with 2 days of fever, "coke"-colored urine, and jaundice. The pregnancy was uneventful except the infant was found to have hyperbilirubinemia that was treated with phototherapy. The mother explains that she breastfeeds her child and recently was treated herself for a UTI with trimethoprim-sulfamethoxazole (TMP-SMX). Which of the following diseases is similarly inherited as the disease experienced by the child?

Q10

A 6-month-old boy is brought to a pediatrician by his parents for his first visit after they adopt him from a European country. His parents are concerned about the boy’s short episodes of shaking of his arms and legs; they believe it might be epilepsy. They also note that the child is less responsive than other children of his age. The family is unable to provide any vaccination, birth, or family history. His pulse is 130/min, respiratory rate is 28/min, and blood pressure is 90/50 mm Hg. The boy has a light skin tone and emits a noticeable musty body odor. Which of the following should be supplemented in this patient’s diet?

Mucopolysaccharidoses US Medical PG Practice Questions and MCQs

Question 1: A 5-month-old boy is brought to his pediatrician because his parents have noticed that he has very restricted joint movement. He was born at home without prenatal care, but they say that he appeared healthy at birth. Since then, they say that he doesn't seem to move very much and is hard to arouse. Physical exam reveals coarse facial structures and hepatosplenomegaly. Radiography reveals skeletal malformations, and serum tests show high plasma levels of lysosomal enzymes. The production of which of the following substances will most likely be disrupted in this patient?

A. Glucocerebroside
B. Mannose-6-phosphate (Correct Answer)
C. Heparan sulfate
D. Ceramide

Explanation: ***Mannose-6-phosphate*** - The patient's symptoms (restricted joint movement, coarse facial features, hepatosplenomegaly, skeletal malformations, and high plasma levels of lysosomal enzymes) are highly suggestive of **I-cell disease (mucolipidosis type II)**. - I-cell disease is caused by a deficiency in the enzyme **N-acetylglucosaminyl-1-phosphotransferase**, which is responsible for phosphorylating mannose residues to create **mannose-6-phosphate (M6P)** tags; this tag is crucial for directing lysosomal enzymes to the lysosome. Without these tags, lysosomal enzymes are secreted extracellularly (hence high plasma levels) instead of being delivered to lysosomes, leading to accumulation of undigested substrates within lysosomes. *Glucocerebroside* - This is a substrate that accumulates in **Gaucher disease**, a **lysosomal storage disorder** caused by a deficiency in glucocerebrosidase. - While Gaucher disease involves hepatosplenomegaly and skeletal issues, it does not typically present with the coarse facial features, severe joint restriction, or widespread undigested lysosomal enzymes in the plasma seen in this patient. *Heparan sulfate* - **Heparan sulfate** is a **glycosaminoglycan** that accumulates in certain mucopolysaccharidoses (e.g., Sanfilippo syndrome, Hurler syndrome). - While mucopolysaccharidoses also present with coarse facial features, skeletal abnormalities, and hepatosplenomegaly, they are caused by defects in the enzymes that degrade glycosaminoglycans, not a defect in the lysosomal enzyme targeting mechanism itself as suggested by the high plasma lysosomal enzymes. *Ceramide* - **Ceramide** is a **lipid precursor** to sphingolipids and glycosphingolipids, which accumulate in various lysosomal storage diseases (e.g., Farber disease). - While numerous lysosomal storage disorders involve improper ceramide metabolism or its derivatives, a primary defect in ceramide production or breakdown as the root cause for the entire clinical picture with high plasma lysosomal enzymes is less likely than the targeting defect in I-cell disease.

Question 2: An 18-month-old girl is brought to the pediatrician’s office for failure to thrive and developmental delay. The patient’s mother says she has not started speaking and is just now starting to pull herself up to standing position. Furthermore, her movement appears to be restricted. Physical examination reveals coarse facial features and restricted joint mobility. Laboratory studies show increased plasma levels of several enzymes. Which of the following is the underlying biochemical defect in this patient?

A. Congenital lack of lysosomal formation
B. Inappropriate protein targeting to endoplasmic reticulum
C. Failure of mannose phosphorylation (Correct Answer)
D. Inappropriate degradation of lysosomal enzymes
E. Misfolding of nuclear proteins

Explanation: ***Failure of mannose phosphorylation*** - The constellation of **failure to thrive**, **developmental delay**, **coarse facial features**, restricted joint mobility, and elevated plasma enzymes in an 18-month-old girl is highly suggestive of **I-cell disease** (mucolipidosis type II). - **I-cell disease** is caused by the deficiency of **N-acetylglucosaminyl-1-phosphotransferase**, an enzyme responsible for phosphorylating mannose residues on lysosomal enzymes, which is crucial for proper targeting to the lysosome. *Congenital lack of lysosomal formation* - **Lysosomes** are present in this condition, but their enzymes are misdirected. - A congenital lack of lysosomal formation would present with even more severe and widespread cellular dysfunction, possibly incompatible with life beyond early embryonic stages. *Inappropriate protein targeting to endoplasmic reticulum* - Proteins destined for the endoplasmic reticulum (ER) are typically targeted by an N-terminal signal peptide and then processed within the ER. - While ER dysfunction can cause various disorders, the specific symptoms and enzyme elevations point away from a primary ER targeting defect related to lysosomal enzymes. *Inappropriate degradation of lysosomal enzymes* - In I-cell disease, lysosomal enzymes are synthesized but are **not properly targeted to the lysosomes**; instead, they are secreted into the bloodstream, leading to their elevated plasma levels. - While some degradation might occur, the primary issue is mis-packaging and secretion, not increased degradation within the cell. *Misfolding of nuclear proteins* - Misfolding of nuclear proteins can lead to a variety of genetic disorders and cellular stress responses, but the clinical presentation, particularly the accumulation of undegraded material and elevated plasma lysosomal enzymes, is not characteristic of primary nuclear protein misfolding. - The pathology in I-cell disease centers on lysosomal dysfunction rather than nuclear protein abnormalities.

Question 3: An 18-month-old boy is brought in by his parents for a routine check-up. The parents state that the patient still has not had any language development, and they are concerned about developmental delay. Of note, they have also noticed that the patient’s facial features have changed significantly in the last year. The patient also seems to have trouble visually focusing on objects or on the television. On exam, the patient's temperature is 98.2°F (36.8°C), blood pressure is 108/72 mmHg, pulse is 86/min, and respirations are 14/min. Of interest, the patient has not increased much in length or weight in the past 3 months. He is now in the 25th percentile for weight but is in the 90th percentile for head circumference. The patient does not appear to have any gross or fine motor deficiencies. Of note, he has coarse facial features that were not previously noted, including a long face, prominent forehead, and protruding eyes. The patient has corneal clouding bilaterally. At rest, the patient keeps his mouth hanging open. After extensive workup, the patient is found to have 2 mutated copies of the IDUA gene, with no production of the protein iduronidase. Which of the following is the likely mutation found in this disease?

A. Interstitial deletion
B. Silent mutation
C. Missense mutation
D. Chromosomal translocation
E. Nonsense mutation (Correct Answer)

Explanation: ***Nonsense mutation*** - A **nonsense mutation** leads to the formation of a **premature stop codon**, resulting in a truncated, non-functional protein, which aligns with the total absence of iduronidase. - This type of mutation can severely impair protein function, leading to the severe phenotype described with **Hurler syndrome**, which is caused by a complete lack of **alpha-L-iduronidase** activity due to mutations in the *IDUA* gene. *Interstitial deletion* - An **interstitial deletion** involves the loss of a segment of a chromosome; while it can cause genetic disorders, it typically results in the **complete absence of a gene** or multiple genes, not specific protein truncation from a gene sequence. - Though a deletion in the *IDUA* gene could cause Hurler syndrome, the specific finding of **no production of the protein iduronidase** suggests a point mutation affecting protein synthesis rather than a large chromosomal deletion. *Silent mutation* - A **silent mutation** is a change in a single nucleotide that does not alter the **amino acid sequence** of the protein due to the redundancy of the genetic code. - This type of mutation would **not cause any change** in protein function or expression, as seen in this patient with complete absence of iduronidase. *Missense mutation* - A **missense mutation** involves a change in a single nucleotide that results in a **different amino acid** being incorporated into the protein. - While a missense mutation can impair protein function, it typically results in a **partially functional** or altered protein, not the complete absence of protein product as described. *Chromosomal translocation* - A **chromosomal translocation** involves the rearrangement of parts between non-homologous chromosomes. - While translocations can lead to genetic disorders by disrupting gene function or dosage, they are less likely to cause a **complete absence of a specific enzyme** unless the translocation directly disrupts the gene's coding region or regulatory elements in a way that prevents any transcription or translation.

Question 4: A 4-week-old infant is brought to the physician by his mother because of blood-tinged stools for 3 days. He has also been passing whitish mucoid strings with the stools during this period. He was delivered at 38 weeks' gestation by lower segment transverse cesarean section because of a nonreassuring fetal heart rate. He was monitored in the intensive care unit for a day prior to being discharged. His 6-year-old brother was treated for viral gastroenteritis one week ago. The patient is exclusively breastfed. He is at the 50th percentile for height and 60th percentile for weight. He appears healthy and active. His vital signs are within normal limits. Examination shows a soft and nontender abdomen. The liver is palpated just below the right costal margin. The remainder of the examination shows no abnormalities. Test of the stool for occult blood is positive. A complete blood count and serum concentrations of electrolytes and creatinine are within the reference range. Which of the following is the most appropriate next step in management?

A. Perform stool antigen immunoassay
B. Perform an air enema on the infant
C. Assess for IgA (anti‑)tissue transglutaminase antibodies (tTG)
D. Stop breastfeeding and switch to soy-based formula
E. Continue breastfeeding and advise mother to avoid dairy and soy products (Correct Answer)

Explanation: ***Continue breastfeeding and advise mother to avoid dairy and soy products*** - The infant's symptoms of **blood-tinged stools** and **mucoid strings**, along with a positive occult blood test, in an otherwise healthy, exclusively breastfed infant point towards **food protein-induced proctocolitis (FPIAP)**. - The most common triggers for FPIAP are **cow's milk protein** and **soy protein** from the maternal diet transmitted through breast milk. The initial management involves the mother eliminating these proteins from her diet. *Perform stool antigen immunoassay* - This test is used to detect specific viral, bacterial, or parasitic antigens in stool, often for conditions like **rotavirus, giardiasis, or C. difficile**. - The infant's clinical presentation with **no fever, vomiting, or diarrhea**, and an otherwise healthy appearance, makes an infectious cause less likely compared to FPIAP. *Perform an air enema on the infant* - An air enema is primarily a diagnostic and therapeutic intervention for **intussusception**, a condition where one segment of the intestine telescopes into another. - Intussusception typically presents with sudden onset of severe, colicky abdominal pain, **"currant jelly" stools**, and often a palpable abdominal mass, none of which are described in this infant. *Assess for IgA (anti‑)tissue transglutaminase antibodies (tTG)* - This test is used to screen for **celiac disease**, an autoimmune disorder triggered by gluten consumption. - Celiac disease typically presents after the introduction of **gluten-containing foods** into the diet, usually around 6-12 months of age, and is characterized by malabsorption symptoms like diarrhea, weight loss, and failure to thrive, which are absent here. *Stop breastfeeding and switch to soy-based formula* - Stopping breastfeeding is generally **not recommended** as breast milk provides numerous benefits. - Switching to a **soy-based formula** may not resolve the issue, as many infants with cow's milk protein allergy also have a **soy protein allergy**. The preferred approach is to eliminate allergens from the maternal diet while continuing breastfeeding.

Question 5: A 4-month-old boy is brought to the emergency department by his mother because of lethargy and vomiting since he woke up 1 hour ago. The mother says that he last breastfed the previous evening and slept through the night for the first time. His family recently immigrated from Bolivia. His temperature is 38.7°C (101.2°F). Physical examination shows dry mucous membranes and enlarged, reddened tonsils. Serum studies show: Glucose 42 mg/dL Ketones 0.2 mg/dL N = < 1 mg/dL AST 40 U/L ALT 60 U/L Ammonia 80 μ/dL (N=15–45) Which of the following enzymes is most likely deficient in this patient?

A. Galactose-1-phosphate uridyltransferase
B. Medium-chain acyl-CoA dehydrogenase (Correct Answer)
C. Alpha-L-iduronidase
D. Propionyl-CoA carboxylase
E. Lysosomal acid α-1,4- glucosidase

Explanation: ***Medium-chain acyl-CoA dehydrogenase*** - The patient presents with **hypoglycemia** (glucose 42 mg/dL) and **hypoketonemia** (ketone 0.2 mg/dL) after a prolonged fast, which are classic signs of a **fatty acid oxidation disorder**. - **Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency** leads to impaired breakdown of medium-chain fatty acids, crucial for energy production during fasting, resulting in symptoms like **lethargy**, **vomiting**, and **metabolic derangements**. *Galactose-1-phosphate uridyltransferase* - Deficiency of this enzyme causes **classic galactosemia**, presenting with **vomiting**, **jaundice**, **hepatomegaly**, and **cataracts** upon introduction of lactose in the diet. - While vomiting is present, the key features like jaundice and cataracts are absent, and the primary metabolic issue is not related to glucose and ketone levels in the context of fasting. *Alpha-L-iduronidase* - This enzyme deficiency causes **Hurler syndrome (MPS I)**, a lysosomal storage disease characterized by **coarse facial features**, **skeletal abnormalities**, **hepatosplenomegaly**, and **developmental delay**. - The patient's acute presentation with hypoglycemia and hypoketonemia does not align with the typical long-term, progressive features of a mucopolysaccharidosis. *Propionyl-CoA carboxylase* - Deficiency of this enzyme leads to **propionic acidemia**, a type of **organic acidemia**, typically presenting with **ketoacidosis** (elevated ketones), metabolic acidosis, hyperammonemia, and neurological symptoms like seizures and lethargy. - The patient's **hypoketonemia** is the key distinguishing feature that rules this out; propionic acidemia presents with elevated ketones, not reduced ketones as seen in fatty acid oxidation disorders. *Lysosomal acid α-1,4-glucosidase* - Deficiency of this enzyme causes **Pompe disease (glycogen storage disease type II)**, which leads to accumulation of glycogen primarily in muscle and liver, resulting in **cardiomyopathy**, **hypotonia**, and **hepatomegaly**. - While it is a metabolic disorder, the clinical picture of severe hypoglycemia and hypoketonemia after fasting is not the hallmark of Pompe disease; instead, muscle weakness and cardiac issues dominate.

Question 6: A deficiency in which of the following lysosomal enzymes is inherited in a pattern similar to a deficiency of iduronate sulfatase (Hunter syndrome)?

A. Sphingomyelinase
B. Glucocerebrosidase
C. Galactocerebrosidase
D. Alpha-L-iduronidase
E. Alpha-galactosidase A (Correct Answer)

Explanation: ***Alpha-galactosidase A*** - A deficiency in **alpha-galactosidase A** causes **Fabry disease**, which, like Hunter syndrome (iduronate sulfatase deficiency), is inherited in an **X-linked recessive** pattern. - Both conditions primarily affect males, with carrier females potentially exhibiting milder symptoms. *Sphingomyelinase* - A deficiency in sphingomyelinase leads to **Niemann-Pick disease types A and B**, which are inherited in an **autosomal recessive** pattern. - This mode of inheritance differs from the X-linked pattern of Hunter syndrome. *Glucocerebrosidase* - A deficiency in glucocerebrosidase causes **Gaucher disease**, inherited in an **autosomal recessive** pattern. - This is a common lysosomal storage disorder, but its inheritance pattern is distinct from X-linked disorders. *Galactocerebrosidase* - A deficiency in galactocerebrosidase causes **Krabbe disease (globoid cell leukodystrophy)**, which is inherited in an **autosomal recessive** pattern. - Krabbe disease is a severe neurodegenerative disorder, but its genetic transmission is not X-linked. *Alpha-L-iduronidase* - A deficiency in **alpha-L-iduronidase** causes **Hurler syndrome (MPS I)**, which is inherited in an **autosomal recessive** pattern. - While both Hunter and Hurler syndromes are mucopolysaccharidoses, their genetic inheritance patterns are different.

Question 7: A 6-month-old boy is referred to a geneticist after he is found to have persistent hypotonia and failure to thrive. He has also had episodes of what appears to be respiratory distress and has an enlarged heart on physical exam. There is a family history of childhood onset hypertrophic cardiomyopathy, so a biopsy is performed showing electron dense granules within the lysosomes. Genetic testing is performed showing a defect in glycogen processing. A deficiency in which of the following enzymes is most likely to be responsible for this patient's symptoms?

A. Lysosomal alpha 1,4-glucosidase (Correct Answer)
B. Branching enzyme
C. Muscle phosphorylase
D. Debranching enzyme
E. Glucose-6-phosphatase

Explanation: ***Lysosomal alpha 1,4-glucosidase*** - The constellation of **hypotonia**, **failure to thrive**, **respiratory distress**, and **cardiomegaly** in an infant, along with **electron-dense granules in lysosomes** and a defect in **glycogen processing**, is characteristic of **Pompe disease (Type II glycogen storage disease)**. - **Pompe disease** is caused by a deficiency of **lysosomal alpha 1,4-glucosidase** (also known as acid maltase), which is responsible for breaking down glycogen in lysosomes. *Branching enzyme* - A deficiency in **branching enzyme (amylo-alpha-1,4-to-alpha-1,6-transglucosidase)** causes **Andersen disease (Type IV glycogen storage disease)**, which typically presents with **hepatosplenomegaly**, **cirrhosis**, and **failure to thrive**. - While it involves glycogenopathy, the specific features of **cardiomyopathy** and **lysosomal accumulation** are not primary to this disorder. *Muscle phosphorylase* - A deficiency in **muscle phosphorylase** causes **McArdle disease (Type V glycogen storage disease)**, which primarily affects **skeletal muscle**. - Symptoms include **exercise intolerance**, **muscle cramps**, and **myoglobinuria**, typically presenting later in childhood or adolescence, and does not involve cardiomyopathy or lysosomal storage. *Debranching enzyme* - A deficiency in **debranching enzyme (alpha-1,6-glucosidase)** causes **Cori disease (Type III glycogen storage disease)**, which presents with **hepatomegaly**, **hypoglycemia**, and **muscle weakness**. - While it can sometimes involve a milder form of cardiomyopathy, the significant **lysosomal involvement** and severe infantile onset with respiratory distress and profound hypotonia point away from Cori disease. *Glucose-6-phosphatase* - A deficiency in **glucose-6-phosphatase** causes **Von Gierke disease (Type I glycogen storage disease)**, characterized by **severe fasting hypoglycemia**, **lactic acidosis**, **hepatomegaly**, and **hyperlipidemia**. - This condition primarily affects the liver and kidneys, and typically does not present with primary cardiomyopathy, hypotonia, or lysosomal glycogen accumulation.

Question 8: A 9-month-old girl is brought to the physician because of a 1-month history of poor feeding and irritability. She is at the 15th percentile for height and 5th percentile for weight. Examination shows hypotonia and wasting of skeletal muscles. Cardiopulmonary examination shows no abnormalities. There is hepatomegaly. Her serum glucose is 61 mg/dL, creatinine kinase is 100 U/L, and lactic acid is within the reference range. Urine ketone bodies are elevated. Which of the following enzymes is most likely deficient in this patient?

A. Glucose-6-phosphatase
B. Muscle phosphorylase
C. Acid alpha-glucosidase
D. Glycogen debrancher (Correct Answer)
E. Glucocerebrosidase

Explanation: ***Glycogen debrancher*** - The patient's symptoms of **hepatomegaly**, **hypoglycemia**, **poor feeding**, **growth failure**, and **elevated urine ketones** in the presence of normal lactic acid suggest Type III glycogen storage disease (Cori disease), caused by a deficiency in **glycogen debrancher enzyme**. - **Muscle wasting** and **hypotonia** are also consistent with Type III GSD, as the debranching enzyme is present in both liver and muscle. *Glucose-6-phosphatase* - Deficiency in **glucose-6-phosphatase** (Type I GSD, Von Gierke disease) also presents with **hepatomegaly** and **hypoglycemia**. - However, Type I GSD is characterized by **lactic acidosis**, which is explicitly stated as normal in this patient, and **hyperlipidemia**, which is not mentioned. *Muscle phosphorylase* - Deficiency in **muscle phosphorylase** (Type V GSD, McArdle disease) primarily affects skeletal muscle, causing **exercise intolerance** and **muscle pain**. - It does not typically present with **hypoglycemia**, **hepatomegaly**, or **growth failure** in infancy. *Acid alpha-glucosidase* - Deficiency in **acid alpha-glucosidase** (Type II GSD, Pompe disease) causes accumulation of glycogen in lysosomes, leading to severe **cardiomyopathy**, **hypotonia**, and **muscle weakness**. - While hypotonia is present, the absence of **cardiomegaly** and significant **liver involvement** makes this diagnosis less likely. *Glucocerebrosidase* - Deficiency in **glucocerebrosidase** causes Gaucher disease, a lysosomal storage disorder, not a glycogen storage disorder. - Symptoms include **hepatosplenomegaly**, **bone crises**, and neurological symptoms, but not **hypoglycemia** or isolated muscle wasting directly related to glycogen metabolism.

Question 9: A 3-month-old African American infant presents to the hospital with 2 days of fever, "coke"-colored urine, and jaundice. The pregnancy was uneventful except the infant was found to have hyperbilirubinemia that was treated with phototherapy. The mother explains that she breastfeeds her child and recently was treated herself for a UTI with trimethoprim-sulfamethoxazole (TMP-SMX). Which of the following diseases is similarly inherited as the disease experienced by the child?

A. Hemophilia A (Correct Answer)
B. Rett syndrome
C. Beta thalassemia
D. Sickle cell anemia
E. Marfan syndrome

Explanation: ***Hemophilia A*** - The infant's symptoms (**fever**, **coke-colored urine**, **jaundice**, and history of **hyperbilirubinemia**) following exposure to **trimethoprim-sulfamethoxazole (TMP-SMX)** suggest **glucose-6-phosphate dehydrogenase (G6PD) deficiency**, an X-linked recessive condition. - **Hemophilia A** is also an **X-linked recessive disorder**, making its inheritance pattern similar to G6PD deficiency. *Rett syndrome* - **Rett syndrome** is an **X-linked dominant** neurodevelopmental disorder, primarily affecting females severely and often embryonically lethal in males. - Its inheritance pattern differs significantly from the X-linked recessive inheritance of G6PD deficiency. *Beta thalassemia* - **Beta thalassemia** is an **autosomal recessive** blood disorder, meaning it is inherited through genes located on non-sex chromosomes. - This inheritance pattern is distinct from the X-linked recessive pattern of G6PD deficiency. *Sickle cell anemia* - **Sickle cell anemia** is an **autosomal recessive** hereditary blood disorder, with the gene located on chromosome 11. - Its inheritance pathway is different from the X-linked recessive genetic inheritance seen in G6PD deficiency. *Marfan syndrome* - **Marfan syndrome** is an **autosomal dominant** disorder affecting connective tissue, the gene for which is located on chromosome 15. - This mode of inheritance is distinctly different from the X-linked recessive pattern of inheritance.

Question 10: A 6-month-old boy is brought to a pediatrician by his parents for his first visit after they adopt him from a European country. His parents are concerned about the boy’s short episodes of shaking of his arms and legs; they believe it might be epilepsy. They also note that the child is less responsive than other children of his age. The family is unable to provide any vaccination, birth, or family history. His pulse is 130/min, respiratory rate is 28/min, and blood pressure is 90/50 mm Hg. The boy has a light skin tone and emits a noticeable musty body odor. Which of the following should be supplemented in this patient’s diet?

A. Isoleucine
B. Leucine
C. Tyrosine (Correct Answer)
D. Phenylalanine
E. Histidine

Explanation: ***Tyrosine*** - The patient's presentation with **seizures**, **developmental delay** (less responsive), **light skin tone**, and a **musty body odor** is highly suggestive of **phenylketonuria (PKU)**. - In PKU, there is a deficiency in the enzyme **phenylalanine hydroxylase**, which converts **phenylalanine** to **tyrosine**. Therefore, **tyrosine** becomes an **essential amino acid** and must be supplemented in the diet. *Isoleucine* - **Isoleucine** is a **branched-chain amino acid** that is typically restricted, along with leucine and valine, in conditions like **maple syrup urine disease (MSUD)**, not PKU. - Supplementation of isoleucine would be detrimental in MSUD and is not indicated for PKU. *Leucine* - Similar to isoleucine, **leucine** is a **branched-chain amino acid** whose metabolism is impaired in **MSUD**, not PKU. - Supplementing leucine is not beneficial for PKU and would be harmful in MSUD. *Phenylalanine* - **Phenylalanine** is the amino acid that accumulates to toxic levels in **PKU** due to the enzyme deficiency. - Therefore, phenylalanine must be **strictly restricted** in the patient's diet, not supplemented. *Histidine* - **Histidine** is an essential amino acid but is not directly involved in the metabolic pathway affected by PKU. - There is no indication for histidine supplementation in the management of PKU.

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