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A 6-month-old boy is brought to the pediatrician by his parents, who are first cousins. This is
their first child. Physical examination reveals a small, thin, lethargic infant with slightly
misshapen long bones. His features are somewhat coarse. Joint movements are restricted, his
corneas are clouded, and his gums are underdeveloped. His liver is not enlarged. Serum levels of
acid hydrolases are found to be elevated. The child most likely has a defect in which of the
following metabolic activities?
A. Degradation of dermatan sulfate and heparan sulfate
B. Degradation of gangliosides
C. Degradation of glycogen
D. Degradation of sphingomyelin
E. Phosphorylation of mannose moieties
F. Phosphorylation of tyrosine moieties
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The correct answer is E. The patient has I-cell disease, also known as mucolipidosis II, which is
due to a defective UDP-N-acetylglucosamine-1-phosphotransferase, the enzyme that
phosphorylates mannose on enzymes destined for lysosomes. Proteins coded by nuclear DNA are
synthesized on cytoplasmic ribosomes, which may be either "free" or associated with the
endoplasmic reticulum to form the rough endoplastic reticulum (RER). Proteins synthesized in
the RER are transferred into the Golgi apparatus, where they undergo further modifications that
determine whether they remain part of the Golgi apparatus, become part of the plasma
membrane, or are shipped to lysosomes or other locations. Proteins not marked for transport to a
specific intracellular site follow the default pathway and are exported into the extracellular
compartment. The signal for transport of the acid hydrolases (and probably other enzymes) to the
lysosomes is phosphorylation of a terminal mannose moiety on an N-linked oligosaccharide to
form mannose 6-phosphate. In I-cell disease, this terminal mannose moiety is not
phosphorylated, and the acid hydrolases follow the default pathway and are secreted.
Deficiency of alpha-L-iduronidase results in lysosomal accumulation of dermatan sulfate and
heparan sulfate (choice A) in several conditions such as mucopolysaccharidosis I, Hurler's
disease, or Hurler's/Scheie disease.
Hexosaminidase A deficiency (Tay-Sachs disease) is one example of a condition in which
ganglioside accumulation occurs (choice B).
There are a number of diseases in which glycogen degradation (choice C) is defective. These are
collectively termed glycogen storage diseases since they result in abnormal cellular accumulation
of glycogen. In Pompe's disease, or type II glycogen storage disease, a lysosomal glucosidase is
deficient, resulting in lysosomal glycogen accumulation.
Deficiency of sphingomyelinase (choice D), an enzyme involved in degradation of
sphingomyelin, results in Niemann-Pick disease.
Phosphorylation of tyrosine moieties (choice F) is unrelated to lysosomes or lysosomal enzymes;
however, decreased ability to phosphorylate tyrosine moieties might be associated with diabetes
or dwarfism.
