An 8-month-old boy is brought to the physician by his parents for gradually increasing loss of neck control and inability to roll over for the past 2 months. During this time, he has had multiple episodes of unresponsiveness with a blank stare and fluttering of the eyelids. His parents state that he sometimes does not turn when called but gets startled by loud noises. He does not maintain eye contact. He was able to roll over from front to back at 5 months of age and has not yet begun to sit or crawl. His parents are of Ashkenazi Jewish descent. Neurological examination shows generalized hypotonia. Deep tendon reflexes are 3+ bilaterally. Plantar reflex shows extensor response bilaterally. Fundoscopy shows bright red macular spots bilaterally. The remainder of the examination shows no abnormalities. Which of the following is the most likely cause of this patient's symptoms?

β-glucocerebrosidase deficiency

ATP-binding cassette transporter mutation

An 18-month-old boy of Ashkenazi-Jewish descent presents with loss of developmental milestones. On ocular exam, a cherry-red macular spot is observed. No hepatomegaly is observed on physical exam. Microscopic exam shows lysosomes with onion-skin appearance. What is the most likely underlying biochemical abnormality?

Accumulation of GM2 ganglioside

Accumulation of ceramide trihexoside

Accumulation of glucocerebroside

Accumulation of galactocerebroside

An 8-month-old female infant from a first-degree consanguineous couple was brought to the physician because the mother noticed abnormalities in the growth of her child as well as the different lengths of her child's legs. The infant had gingival hyperplasia, restricted movement in both shoulders, a prominent, pointed forehead, and enophthalmos with a slight opacity in both corneas. A blood test revealed 10 fold higher than normal levels of the following enzymes: N-acetyl-ß-glucosaminidase, ß-glucuronidase, ß-hexosaminidase A, and alkaline phosphatase. Which of the following is most likely deficient in this patient?

N-acetyl-glucosamine-1-phosphotransferase

Lysosomal alpha-1,4-glucosidase

Glucose-6-phosphate dehydrogenase

A 6-month-old infant male is brought to the emergency department with a 1-hour history of vomiting and convulsions. He was born at home and had sporadic prenatal care though his parents say that he appeared healthy at birth. He initially fed well; however, his parents have noticed that he has been feeding poorly and is very irritable since they moved on to baby foods. They have also noticed mild yellowing of his skin but assumed it would go away over time. On presentation, he is found to be very sleepy, and physical exam reveals an enlarged liver and spleen. The rest of the physical exam is normal. Which of the following enzymes is most likely functioning abnormally in this patient?

Gal-1-phosphate uridyl transferase

A research study evaluates three siblings with Niemann-Pick disease type C: a 6-year-old with ataxia and vertical supranuclear gaze palsy, a 10-year-old with hepatosplenomegaly and mild cognitive impairment, and a 14-year-old who is asymptomatic. Genetic testing reveals all three carry the same compound heterozygous NPC1 mutations. Fibroblast studies show similar cholesterol esterification defects and filipin staining patterns. Miglustat therapy is available. Evaluate the biological basis for phenotypic variability and optimal treatment allocation.

Evaluate modifier genes, epigenetic factors, and biomarkers; treat based on individual risk stratification

Treat all three immediately as genetic identity predicts identical disease course

Treat only symptomatic siblings as asymptomatic carrier won't develop disease

Delay all treatment until symptoms appear in the youngest to confirm diagnosis

Treat the 6-year-old only as neurologic symptoms indicate blood-brain barrier dysfunction

Sphingolipidoses (Tay-Sachs, Gaucher, Niemann-Pick) for USMLE Step 2 CK: High-Yield Biochemistry Lessons

Sphingolipidoses - The Lipid Burglars

Autosomal recessive lysosomal storage diseases from deficient enzymes in sphingolipid metabolism, causing substrate accumulation with neurotoxicity and organomegaly.
Tay-Sachs: Deficient Hexosaminidase A → ↑ GM2 ganglioside. Features a "cherry-red" macula but no hepatosplenomegaly.
Gaucher: Deficient Glucocerebrosidase → ↑ Glucocerebroside. Causes hepatosplenomegaly, pancytopenia, and bone crises.
Niemann-Pick: Deficient Sphingomyelinase → ↑ Sphingomyelin. Presents with a "cherry-red" macula and hepatosplenomegaly.

⭐ Gaucher cells, the hallmark of Gaucher disease, are lipid-laden macrophages with a "crinkled tissue paper" appearance.

Gaucher and Niemann-Pick Cells: Illustrations and Histology

Tay-Sachs Disease - Ganglioside Overload

Deficient Enzyme: Hexosaminidase A
Accumulated Substrate: GM2 Ganglioside
Key Features:
- Progressive neurodegeneration starting at age 3-6 months.
- Exaggerated startle response (hyperacusis).
- NO hepatosplenomegaly (key differentiator from Niemann-Pick).
Ocular Finding: Cherry-red spot on macula.

Cherry-red, brown, and black spots in lysosomal diseases

⭐ Lysosomes with an "onion skin" appearance are a classic ultrastructural finding on electron microscopy.

📌 Mnemonic: TAY-SaX lacks HeXosaminidase A.

Gaucher Disease - Crinkled Paper Crisis

Deficient Enzyme: Glucocerebrosidase (β-glucosidase).
Accumulated Substrate: Glucocerebroside.
Key Features:
- Massive hepatosplenomegaly.
- Pancytopenia (anemia, thrombocytopenia → easy bruising).
- Severe bone pain, bone crises, and aseptic necrosis of the femur.
Histology: Gaucher cells - lipid-laden macrophages with a "crinkled tissue paper" appearance.

Gaucher cells with wrinkled tissue pattern, bone marrow

⭐ Gaucher disease is the most common lysosomal storage disease, with a significantly higher prevalence in Ashkenazi Jewish populations.

Niemann-Pick Disease - Foamy & Fierce

Deficient Enzyme: Sphingomyelinase
Accumulated Substrate: Sphingomyelin
Key Features: Combines progressive neurodegeneration with significant hepatosplenomegaly.
Histology: Foam cells (lipid-laden macrophages) are pathognomonic.
Ocular Finding: Cherry-red spot on macula, present in ~50% of cases.

📌 Mnemonic: Pick your nose with your sphinger (sphingomyelinase).

⭐ Type A is the severe, infantile-onset form with profound neurodegeneration, while Type B presents later with massive hepatosplenomegaly but no primary CNS involvement.

High‑Yield Points - ⚡ Biggest Takeaways

Tay-Sachs vs. Niemann-Pick: Both have a cherry-red spot on the macula, but only Niemann-Pick presents with hepatosplenomegaly.

Gaucher disease is the most common, characterized by massive splenomegaly, pancytopenia, and bone crises.

Note the key enzyme deficiencies: Hexosaminidase A in Tay-Sachs, Sphingomyelinase in Niemann-Pick, and Glucocerebrosidase in Gaucher.

Look for classic microscopic findings: "crinkled tissue paper" cytoplasm in Gaucher cells and "foamy" macrophages in Niemann-Pick.

All three are autosomal recessive with a higher prevalence in Ashkenazi Jewish populations.

Continue reading on Oncourse

CONTINUE READING — FREE

or get the app

App Store|Google Play