An 18-month-old boy is brought to clinic due to difficulty walking. The patient began walking around age 12 months but his mother recently noticed he has difficulty maintaining his balance and often falls after a few steps. Weight is at the 15th percentile and height is at the 5th percentile. Examination shows increased tone with occasional muscle spasms in the lower extremities. Abdominal examination shows hepatosplenomegaly. Laboratory results reveal decreased glucocerebrosidase activity. This patient's enzyme deficiency is most likely impairing the function of which of the following organelles?
Sphingolipidoses* | ||||
Diagnosis | Inheritance | Deficiency | Accumulated substrate | Key features |
Fabry disease | XLR | α-Galactosidase A | Globotriaosylceramide |
|
Tay-Sachs disease | AR | β-Hexosaminidase A | GM2 (ganglioside) |
|
Gaucher disease | β-Glucocerebrosidase | Glucocerebroside |
| |
Niemann-Pick disease | Sphingomyelinase | Sphingomyelin |
| |
Krabbe disease | Galactocerebrosidase | Galactocerebroside & psychosine |
| |
Metachromatic leukodystrophy | Arylsulfatase A | Cerebroside sulfate |
| |
| * Subtype of lysosomal storage disorder. AR = autosomal recessive; XLR = X-linked recessive. | ||||
Glucocerebrosidase is an acid hydrolase (enzyme active at a low pH) that is found within lysosomes; it is responsible for the breakdown of glucocerebroside, a component of cell membranes. Decreased activity of this enzyme occurs in Gaucher disease and results in the accumulation of glucocerebroside in lysosomes, which disrupts cellular function. Because mononuclear phagocytes (eg, macrophages) engulf cellular debris and extracellular matrix components, they are affected in most lysosomal storage diseases (eg, sphingolipidoses, mucopolysaccharidoses), including Gaucher disease.
In Gaucher disease, macrophages in the liver, spleen, and bone are predominantly affected, resulting in marked hepatosplenomegaly (as seen here), bone marrow replacement (eg, anemia, thrombocytopenia), bone pain, and poor growth (eg, height ≤5th percentile). The CNS is also susceptible to glucocerebroside accumulation, and some patients may have neurologic manifestations such as this child's spasticity, muscle spasms, and loss of motor skills.
(Choices A and F) Golgi apparatus defects lead to improper sorting and post-translational glycosylation of cellular proteins, and ribosomal abnormalities would result in deficient protein production. Decreased glucocerebrosidase activity is not associated with such defects.
(Choice C) The mitochondria are responsible for ATP production, and diseases due to abnormal mitochondrial function most commonly lead to muscle weakness, hypotonia, and encephalopathy. Mitochondrial diseases are not associated with decreased glucocerebrosidase activity.
(Choice D) Enzymes within peroxisomes are critical in very long-chain fatty acid oxidation. Enzyme deficiencies, such as in X-linked adrenoleukodystrophy, can result in progressive neurodegeneration and adrenal insufficiency. Glucocerebrosidase is a lysosomal, not peroxisomal, enzyme.
(Choice E) Proteasomes degrade unwanted and misfolded proteins as well as foreign intracellular proteins for display on major histocompatibility complex (MHC) class I molecules. Proteosome dysfunction can lead to protein aggregation but is not associated with glucocerebrosidase deficiency.
Educational objective:
Gaucher disease is a lysosomal storage disease in which decreased activity of glucocerebrosidase leads to a buildup of glucocerebroside. Accumulation of this substrate within lysosomes in the mononuclear phagocyte system classically results in hepatosplenomegaly, cytopenia, and bone pain; CNS involvement can also lead to neurologic manifestations (eg, spasticity).