History:

A six-year-old child is evaluated because of an enlarged abdomen. Physical examination reveals hepatosplenomegaly and lymphadenopathy. There is no history of recent infection. The child's vital signs are: T 36.3 C, R 16, P 77, BP 90/60 mm Hg. Developmental milestones are normal, and the child is doing well in the first year of school. A complete blood count is performed and shows WBC count 2300/microliter, Hgb 10.6 g/dL, Hct 32.4%, MCV 94, and platelet count 83,000/microliter. A bone marrow biopsy is performed. Later, a splenectomy is performed.

Pathologic findings include splenomegaly and red pulp infiltrated by numerous groups of large, pale staining cells. The pale cells have a "wrinkled paper" appearance to the cytoplasm, without vacuoles.

Questions:

1. What is the underlying inherited disease process? What is the pattern of inheritance?

This is Gaucher's disease, the most common lysosomal storage disease. It is an autosomal recessive disorder resulting from genetic mutations encoding the glucocerebrosidase enzyme. Decreased or absent enzyme activity leads to storage of glucocerebrosides in macrophages.

There are three forms of the disease:

• Type 1, the non-neuropathic form, has storage of glucocerebrosides limited to the mononuclear phagocyte system, predominantly skeletal, liver, and splenic, with mild perivascular accumulations in the brain.

• Type 2 is the acute infantile neuronopathic form with infants presenting by 6 months with splenomegaly, failure to thrive and motor delays. Death is at an early age.

• Type 3 has a severity between types 1 and 2, with neurologic deterioration in adolescence to young adulthood.

Most patients (94%) have type 1 GD, fewer than 1% have type 2, and 5% have type 3. Over 100 mutant alleles have been identified in affected patients, but four alleles, termed N370S (53%), L444P (18%), 84GG (7%), and IVS2 (2%), have significant frequencies in this population. In affected patients the presence of a single N370S allele is diagnostic of the type 1 or non-neuronopathic variant, whereas the L444P/L444P genotype is highly associated with neuronopathic variants in the Caucasian population.

2. What is the biochemical defect?

The lack of glucocerebrosidase leads to accumulation of glucocerebroside, mostly in macrophages in organs of the mononuclear phagocyte system (marrow, spleen, nodes, liver) resulting in hepatosplenomegaly and lymphadenopathy. In severe cases, neurons also are affected. The abnormal accumulation occurs in lysosomes within the macrophages.

The appearance of the cells seen in the spleen in this case is typical of a storage disease--large and pale--leading to organomegaly. Biochemical tests can be performed to determine the specific defect. In some cases, such tests can be done from fibroblasts obtained by amniocentesis to make a diagnosis in utero.

The major sphingolipidoses are (disease, absent enzyme, tissues affected):

Disease	Enzyme	Affected Organs
Tay-Sachs disease	Hexosaminidase A	CNS and Eye
Gaucher's disease	Glucocerebrosidase	Mononuclear phagocyte system and CNS if severe
Niemann-Pick disease	Sphingomyelinase	Mononuclear phagocyte system and CNS



3. What is the significance of the child's performance in school? What does this indicate regarding the prognosis?

The child's cerebral function suggests that there is a mild form of the disease present, type I, the non-neuropathic form, with storage of glucocerebrosides limited to the mononuclear phagocyte system, predominantly marrow, liver, and spleen. This form accounts for 94% of cases.

4. What would you expect to find in a more severe form of this disease?

The type II form of Gaucher's disease, the acute infantile neuronopathic form, has involvement of the central nervous system (brain), and affected infants present by 6 months with splenomegaly, failure to thrive and delayed motor development. Death is at an early age. There is also a rare type III which has a severity between types 1 and 2, with neurologic deterioration in adolescence to young adulthood.