USMLE Step 1 Biochemistry Questions: Lysosomal Storage Diseases – Tay-Sachs, Fabry and Gaucher

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Lysosomal storage diseases are a favorite USMLE Step 1 topic because each one links a deficient enzyme, an accumulated substance and a classic clinical clue. These three practice questions cover Tay-Sachs, Fabry and Gaucher disease. Pick your answer first, then open the explanation.

Question 1: An infant with a cherry-red spot and an exaggerated startle

A 6-month-old boy of Ashkenazi Jewish descent is brought to the physician because he has lost the ability to sit and roll over. He startles excessively to loud noises. Fundoscopic examination shows a cherry-red spot on the macula of both eyes. The liver and spleen are not enlarged. Deficiency of which of the following enzymes is the most likely cause?

A. Glucocerebrosidase
B. Hexosaminidase A
C. Sphingomyelinase
D. Alpha-galactosidase A
E. Galactocerebrosidase

Correct answer: B. Hexosaminidase A

This is Tay-Sachs disease, an autosomal recessive disorder that is more common in people of Ashkenazi Jewish descent. Deficiency of hexosaminidase A leads to accumulation of GM2 ganglioside in neurons, causing progressive neurodegeneration, developmental regression, an exaggerated startle response and a cherry-red spot on the macula. A key clue is the absence of hepatosplenomegaly.

Why the other options are wrong:

  • Glucocerebrosidase deficiency causes Gaucher disease (hepatosplenomegaly, bone crises, Gaucher cells).
  • Sphingomyelinase deficiency causes Niemann-Pick disease, which also has a cherry-red spot but with hepatosplenomegaly and foam cells.
  • Alpha-galactosidase A deficiency causes Fabry disease (X-linked, painful neuropathy, angiokeratomas).
  • Galactocerebrosidase deficiency causes Krabbe disease (globoid cells, optic atrophy, peripheral neuropathy).

 

Question 2: Burning pain in the hands and a rash around the navel

A 32-year-old man has had episodes of burning pain in his hands and feet since childhood, often triggered by fever or exercise. He sweats very little. Examination shows clusters of small, dark red papules around the umbilicus and groin. Urinalysis shows proteinuria. His maternal uncle died of kidney failure at age 45. Accumulation of which of the following substances is responsible for this condition?

A. Glucocerebroside
B. GM2 ganglioside
C. Sphingomyelin
D. Ceramide trihexoside (globotriaosylceramide)
E. Heparan sulfate

Correct answer: D. Ceramide trihexoside (globotriaosylceramide)

This is Fabry disease, an X-linked recessive deficiency of alpha-galactosidase A. Ceramide trihexoside accumulates in nerves, skin, kidneys, heart and blood vessels. Classic findings are episodic peripheral neuropathy (burning pain), angiokeratomas in the “bathing trunk” area, hypohidrosis, and later renal failure and cardiovascular disease. The affected maternal uncle fits X-linked inheritance.

Why the other options are wrong:

  • Glucocerebroside accumulates in Gaucher disease.
  • GM2 ganglioside accumulates in Tay-Sachs disease.
  • Sphingomyelin accumulates in Niemann-Pick disease.
  • Heparan sulfate (with dermatan sulfate) accumulates in Hurler and Hunter syndromes.

 

Question 3: Massive splenomegaly and “crinkled paper” macrophages

A 25-year-old woman has fatigue, easy bruising and episodes of severe bone pain. Examination shows massive splenomegaly and hepatomegaly. Laboratory studies show anemia and thrombocytopenia. X-ray of the distal femur shows an Erlenmeyer flask deformity. A bone marrow biopsy shows macrophages with cytoplasm that looks like crinkled tissue paper. Which of the following is the most appropriate treatment?

A. Hydroxyurea
B. Penicillamine
C. Recombinant glucocerebrosidase (enzyme replacement therapy)
D. Allopurinol
E. Imatinib

Correct answer: C. Recombinant glucocerebrosidase (enzyme replacement therapy)

This is Gaucher disease type 1, the most common lysosomal storage disease. It is autosomal recessive and caused by glucocerebrosidase deficiency, so glucocerebroside builds up in macrophages (Gaucher cells, with “crinkled tissue paper” cytoplasm). Features include hepatosplenomegaly, pancytopenia, bone crises, osteoporosis, avascular necrosis of the femur and Erlenmeyer flask deformity. Treatment is enzyme replacement therapy (e.g., imiglucerase).

Why the other options are wrong:

  • Hydroxyurea is used in sickle cell disease and myeloproliferative disorders.
  • Penicillamine is a copper chelator used in Wilson disease.
  • Allopurinol treats gout and prevents tumor lysis syndrome.
  • Imatinib treats chronic myeloid leukemia (BCR-ABL).

 

Key takeaways

  • Cherry-red spot without hepatosplenomegaly = Tay-Sachs; with hepatosplenomegaly = Niemann-Pick.
  • Fabry disease is X-linked recessive; most other lysosomal storage diseases are autosomal recessive (Hunter syndrome is the other classic X-linked one).
  • Gaucher disease is the most common lysosomal storage disease and is treated with enzyme replacement.

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Written and reviewed by Dr. Ray Makar, MD, dermatologist with 20 years of clinical practice. Last reviewed: October 2026. For exam preparation only, not medical advice.

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