Lysosomal storage diseases

Lysosomal storage diseases US Medical PG Question 1: 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)

Lysosomal storage diseases 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.

Lysosomal storage diseases US Medical PG Question 2: A 7-month-old boy is brought by his parents to the pediatrician’s office. His mother says the child has been weakening progressively and is not as active as he used to be when he was born. His condition seems to be getting worse, especially over the last month. He was born at 41 weeks through normal vaginal delivery. There were no complications observed during the prenatal period. He was progressing well over the 1st few months and achieving the appropriate milestones. On examination, his abdomen appears soft with no liver enlargement. The patient appears to be dehydrated and lethargic. The results of a fundoscopic examination are shown in the picture. A blood test for which of the following enzymes is the next best assay to evaluate this patient's health?

• A. Acid alpha-glucosidase
• B. Hexosaminidase (Correct Answer)
• C. Sphingomyelinase
• D. Glucocerebrosidase
• E. Arylsulfatase A

Lysosomal storage diseases Explanation: ***Hexosaminidase*** - The symptoms and history suggest **Tay-Sachs disease**, characterized by progressive weakness and developmental delay, often linked to **deficiency in hexosaminidase A**. - A fundoscopic exam typically reveals a **cherry-red spot**, consistent with this condition, making hexosaminidase testing essential for diagnosis. - Tay-Sachs results from accumulation of **GM2 ganglioside** in neurons due to hexosaminidase A deficiency. *Glucocerebrosidase* - This enzyme is primarily associated with **Gaucher's disease**, which does not match the clinical features presented here. - Symptoms of Gaucher's disease include **hepatosplenomegaly** and bone pain, not primarily weakness or lethargy in a young infant. *Acid alpha-glucosidase* - Generally tested for **Pompe disease**, which typically presents with **muscle weakness and hypertrophic cardiomyopathy**, not solely lethargy and failure to thrive. - The clinical presentation in this case does not indicate glycogen storage disorder symptoms. *Arylsulfatase A* - This enzyme deficiency relates to **metachromatic leukodystrophy**, which often features neurological decline rather than isolated lethargy in infants. - The specific symptoms and age do not align with the typical findings of this condition. *Sphingomyelinase* - Linked to **Niemann-Pick disease**, characterized by **hepatosplenomegaly** and neurological deterioration, absent in this scenario. - The presentation of weakness does not match the classic signs expected with sphingomyelinase deficiency.

Lysosomal storage diseases US Medical PG Question 3: A 2-year-old boy is brought to the emergency department by his parents because of fever and recurrent episodes of jerky movements of his extremities for the past 6 hours. Pregnancy and delivery were uncomplicated, and development was normal until the age of 1 year. The parents report that he has had gradual loss of speech, vision, and motor skills over the past year. During this time, he has been admitted to the hospital three times because of myoclonic seizures. Physical examination shows hypertonicity of the upper and lower extremities. Fundoscopic examination shows pallor of the optic disc bilaterally. An MRI of the brain shows brain atrophy and hyperintensity of the periventricular and subcortical areas. Two days after admission, the patient dies. Histopathologic examination of the brain shows aggregation of globoid cells and loss of glial cells. The patient’s condition was most likely caused by a deficiency of which of the following enzymes?

• A. β-Galactocerebrosidase (Correct Answer)
• B. β-Glucocerebrosidase
• C. Arylsulfatase A
• D. Sphingomyelinase
• E. β-Hexosaminidase A

Lysosomal storage diseases Explanation: ***β-Galactocerebrosidase*** - The clinical presentation, including the **rapid neurodegeneration** (loss of speech, vision, motor skills), **hypertonicity**, **optic disc pallor**, brain atrophy, and periventricular/subcortical hyperintensities on MRI, is highly consistent with **Krabbe disease**. - The classic histopathologic finding of **globoid cells** (macrophages filled with undigested galactocerebroside) and **loss of glial cells** in the brain are pathognomonic for Krabbe disease, which is caused by a deficiency of **β-galactocerebrosidase**. *β-Glucocerebrosidase* - Deficiency of β-glucocerebrosidase causes **Gaucher disease**, which typically involves **hepatosplenomegaly**, **bone crises**, and **pancytopenia**. - While some forms have neurological involvement, the characteristic globoid cells and rapid neurodegeneration seen here are not typical for Gaucher disease. *Arylsulfatase A* - Deficiency of arylsulfatase A leads to **metachromatic leukodystrophy (MLD)**, which also presents with **progressive neurological deterioration**, motor regression, and demyelination. - However, MLD is characterized by the accumulation of **sulfatides** in white matter and detection of **metachromatic granules** in nerves and urine, not globoid cells. *Sphingomyelinase* - Deficiency of sphingomyelinase causes **Niemann-Pick disease**, which is characterized by **hepatosplenomegaly**, **cherry-red spots** in the macula (in type A), and foam cells in various tissues. - The neurological symptoms and brain pathology in this child are not consistent with Niemann-Pick disease. *β-Hexosaminidase A* - Deficiency of β-hexosaminidase A causes **Tay-Sachs disease**, which presents with **progressive neurodegeneration**, **cherry-red spots** in the macula, and **exaggerated startle response**. - While it causes loss of motor skills and vision, the severe demyelination with periventricular hyperintensities and globoid cells are not features of Tay-Sachs disease (which primarily involves ganglioside accumulation).

Lysosomal storage diseases US Medical PG Question 4: 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)

Lysosomal storage diseases 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.

Lysosomal storage diseases US Medical PG Question 5: A 22-year-old man presents to the physician due to a progressively worsening weakness and an increasingly large abdomen. He notes that he eats well and is fairly active; however, his abdomen has become increasingly protuberant. He also complains of easy bruisability. His medical history is not significant and he takes no medications. Physical examination reveals hepatomegaly and splenomegaly. Several bruises can be seen on the inside of his arms and legs. His skin has a yellowish tinge to it. Laboratory testing shows the following: Hematocrit 25% Erythrocyte count 2.5 x 106/mm3 Thrombocyte count 25,000/mm3 A bone marrow biopsy shows a crinkled-paper appearance to the macrophages. Which of the following enzymes is most likely deficient in this patient?

• A. Arylsulfatase A
• B. Sphingomyelinase
• C. α-galactosidase
• D. Hexosaminidase
• E. β-glucosidase (Correct Answer)

Lysosomal storage diseases Explanation: ***β-glucosidase*** - The patient's symptoms (hepatosplenomegaly, easy bruisability, anemia, thrombocytopenia) and the characteristic **crinkled-paper appearance of macrophages** on bone marrow biopsy are pathognomonic for **Gaucher disease**. - **Gaucher disease** is an autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme **β-glucosidase** (also known as glucocerebrosidase), leading to the accumulation of glucocerebroside. *Arylsulfatase A* - Deficiency of **arylsulfatase A** causes **metachromatic leukodystrophy**, characterized by progressive demyelination and neurological symptoms, not the hematological and visceral findings seen here. - While it is also a lysosomal storage disorder, the clinical presentation and specific cell morphology are distinct. *Sphingomyelinase* - Deficiency of **sphingomyelinase** leads to **Niemann-Pick disease**, which shares some features with Gaucher disease, such as hepatosplenomegaly. - However, the characteristic cell found in Niemann-Pick disease is a lipid-laden macrophage with a **foamy appearance**, not a "crinkled-paper" appearance. *α-galactosidase* - Deficiency of **α-galactosidase A** causes **Fabry disease**, an X-linked lysosomal storage disorder. - Symptoms include episodic pain, acroparesthesias, angiokeratomas, and renal/cardiac involvement, which are not described in this patient. *Hexosaminidase* - Deficiency of **hexosaminidase A** causes **Tay-Sachs disease**, a lysosomal storage disorder primarily affecting the central nervous system. - It is characterized by progressive neurodegeneration, developmental delay, and a **cherry-red spot** on the retina, without the hepatosplenomegaly or characteristic macrophages seen in this case.

Lysosomal storage diseases Flashcard 1 of 5

Question: _____ is a lysosomal storage disease caused by frameshift mutations.

Answer: Tay-Sachs

Lysosomal storage diseases Flashcard 2 of 5

Question: What substrate accumulates in the lysosomes of a patient with Gaucher disease? _____

Answer: Glucocerebroside

Lysosomal storage diseases Flashcard 3 of 5

Question: Which lysosomal storage disease is characterized by a cherry red spot on the macula and hepatosplenomegaly? _____

Answer: Niemann Pick disease

Lysosomal storage diseases Flashcard 4 of 5

Question: Describe, in general, the lysosomal storage diseases.

Answer: Diverse group of diseases resulting from defects in lysosomal enzymes, characterized by an accumulation of abnormal metabolic products within cells.

Lysosomal storage diseases Flashcard 5 of 5

Question: Pompe's disease (GSD type II)

Answer:

Extra Information: heart, liver, muscle manifestations, esp. cardiomegaly; early deathARlysosomal α-1,4-glucosidase (acid maltase)mnemonic: Very Bad Carbohydrate Metabolism (the glycogen storage diseases in order)