A physician-validated, board-style question from the Active Transport QBank. Try it, then check the reasoning for every option.
A 1-year-old boy is brought to his pediatrician for a follow-up appointment. He was recently diagnosed with failure to thrive and developmental delay. His weight is 7 kg (15.4 lb), height is 61 cm (24 in), and head circumference is 42 cm (16.5 in). The patient’s father had a younger sister who suffered from mental and physical delay and died at a very young age. The patient was able to raise his head at the age of 7 months and began to sit alone only recently. He babbles, coos, and smiles to other people. On presentation, his blood pressure is 75/40 mm Hg, heart rate is 147/min, respiratory rate is 28/min, and temperature is 36.4°C (97.5°F). He has a coarse face with small deep orbits, proptotic eyes, big lips, and gingival hyperplasia. His skin is pale with decreased elasticity. His lung and heart sounds are normal. Abdominal examination reveals diminished anterior abdominal wall muscle tone and hepatomegaly. Muscle tone is increased in all groups of muscles on both upper and lower extremities. The physician becomes concerned and performs testing for the suspected hereditary disease. A blood test shows increased lysosomal enzyme concentration in the serum and decreased N-acetylglucosamine-1-phosphotransferase (GlcNAc phosphotransferase) activity within the leukocytes. Which of the statements listed below describes the mechanism of the patient’s condition?
-
A
The patient’s symptoms are due to dysfunctional metabolism of sphingomyelin, which accumulates within the lysosomes.Incorrect. Sphingomyelin accumulation describes Niemann-Pick disease, which presents with hepatosplenomegaly and cherry-red macula — does not match this enzyme-targeting defect.
-
B
There is impaired hydrolysis of GM2-ganglioside, which accumulates in the cytoplasm.Incorrect. GM2 ganglioside accumulation in lysosomes is Tay-Sachs disease, which lacks coarse features or organomegaly.
-
C
The lysosomal enzymes are secreted from the cells instead of being targeted to lysosomes because of lack of mannose phosphorylation on N-linked glycoproteins.Correct. I-cell disease is caused by defective N-acetylglucosamine-1-phosphotransferase, preventing mannose-6-phosphate tagging of lysosomal enzymes; these enzymes are then secreted instead of trafficked to lysosomes.
-
D
The symptoms result from defective glycolysis, which results in a total energy deficiency.Incorrect. Glycolysis defects produce energy deficiency states (e.g., pyruvate kinase deficiency causes hemolytic anemia), not coarse features with elevated serum lysosomal enzymes.
-
E
Deficiency of hexosaminidase A leads to GM2 ganglioside accumulation in neurons.Incorrect. Hexosaminidase A deficiency is Tay-Sachs disease, which presents with cherry-red macula and neurodegeneration without coarse facies, organomegaly, or elevated serum lysosomal enzymes.
↑ Tap an answer to reveal the reasoning
Answer: C. An infant with coarse facial features, gingival hyperplasia, hepatomegaly, developmental delay, and a positive lab finding of ELEVATED lysosomal enzymes in the SERUM with DECREASED N-acetylglucosamine-1-phosphotransferase (GlcNAc phosphotransferase) activity in leukocytes has I-cell disease (mucolipidosis II, inclusion-cell disease). The defect is in the enzyme that adds the mannose-6-phosphate (M6P) targeting tag to newly synthesized lysosomal enzymes in the Golgi. Without M6P, these enzymes cannot be recognized by their receptor and are misrouted: instead of being sent to the lysosome, they are SECRETED into the extracellular space — hence elevated serum levels.
The consequence is lysosomal dysfunction across multiple cell types: undigested substrates accumulate in lysosomes (forming the eponymous 'inclusions'), and patients present in infancy with coarse facies, restricted joint movement, severe psychomotor delay, gingival hyperplasia, and early death (typically by age 7–8).
Distractors test other lysosomal storage diseases:
- Sphingomyelin accumulation: Niemann-Pick disease (acid sphingomyelinase deficiency; cherry-red spot, hepatosplenomegaly).
- GM2-ganglioside accumulation: Tay-Sachs disease (hexosaminidase A deficiency; cherry-red spot, no organomegaly).
- Glycolysis defects: glycogen storage diseases or pyruvate kinase deficiency — different clinical picture.
I-cell disease is the classic 'enzymes in wrong compartment' lysosomal disease.
**Why each option:**
**A.** Sphingomyelin accumulation describes Niemann-Pick disease, which presents with hepatosplenomegaly and cherry-red macula — does not match this enzyme-targeting defect.
**B.** GM2 ganglioside accumulation in lysosomes is Tay-Sachs disease, which lacks coarse features or organomegaly.
**C.** Correct. I-cell disease is caused by defective N-acetylglucosamine-1-phosphotransferase, preventing mannose-6-phosphate tagging of lysosomal enzymes; these enzymes are then secreted instead of trafficked to lysosomes.
**D.** Glycolysis defects produce energy deficiency states (e.g., pyruvate kinase deficiency causes hemolytic anemia), not coarse features with elevated serum lysosomal enzymes.