Gaucher disease

Caused by decreased intracellular hydrolysis of glucosylceramide and other glycosphingolipids associated a result of recessive gene mutations encoding acid ‘-glucosidase (GCase), the lysosomal hydrolase.

Deficiency glucocerebrosidase enzyme.

Type I Gaucher disease is the most common lysosomal storage disease.

In type 1 disease biallelic mutations in GBA (OMIM 606463) result in defective acid beta-glocosidase and cause lysosomal accumulation of glucosylceramide
and glucosylsphingosine, primarily in the monocytes macrophage lineage.

Lipid laden macrophages, that is, Gaucher’s cells, infiltrate the spleen, liver, bone marrow and lungs leading to hepatosplenomegaly pancytopenia, skeletal disease, chronic bone pain, and growth failure.

The incidence of Gaucher disease is relatively confined to certain populations.

In non Jewish populations, the incidence of Gaucher type-1 is 1 in 50,000-75,000 live births.

In Ashkenazi Jewish population, the incidence is estimated to be 1 in 600 live births.

The majority of patients were diagnosed during the fifth decade of life.

Almost two-thirds of Ashkenazi Jews are homozygous for the N370S mutation.

Patients with homozygous N370S disease have the lowest mean severity scores.

Prevalent in Ashkenazi Jews, with an estimated frequency of approximately one in 1000.

In untreated type 1 disease it may be chronic and progressive with reduced life expectancy, and in some patients life-threatening complications.

Results from an autosomal recessive inborn era of metabolism from deficient activity of the degradative enzyme acid beta-glucosidase and the lysosomal accumulation of its glycolsphingolipid substrate glucosylceramide, primarily in the monocyte-macrophage cells of the bone marrow, liver and spleen (Grabowski GA et al).

Clinically presents as hepatosplenomegaly, anemia, thrombocytopenia and bone disease.

Bone pain due to skeletal lesions.

Utilizing enzyme replacement therapy with a macrophage-targeted recombinant beta-glucosidase is effective at ameliorating and preventing the disease process.

Large storage cells in the spleen and bone marrow with massive splenomegaly are the primary clinical characteristics of the disease.

Nearly all affected patients have skeletal involvement with episodic bone infarcts.

Painful bone crises occur in 42% of children below age 10 years and in 25% of persons older than 10.

Increased incidence of multiple myeloma, chronic lymphocytic leukemia, acute myelogenous leukemia, largeB-cell lymphoma, Hodgkin’s lymphoma and non hematologic malignancies.

Approximately 14 fold increase in risk of hematological malignancies (Shiran A et al), but Gaucher registry of 2,742 patients does not show increase in hematological or solid malignancies.

Most patients have plain x-ray film changes of the ‘Erlenmeyer flask’ type deformity.

Mean bone mineral density decreased in adults with nearly universal osteopenia leading to osteoporotic fractures.

Gaucher disease-enzyme therapy for symptomatic patients with human recombinant GCase decreases glucosylceramide accumulation in liver, spleen and bone marrow.

Diagnosed by detection of low enzymatic activity of Beta glucocerebrosidase in peripheral blood cells compared with normal controls.

Bone marrow exam eliminates the suspicion of a malignancy.

The use of GCase results in reduction in severity, frequency and duration of painful bone crises within 1 year of the initiation of treatment.

While the use of GCase therapy stops new lytic lesions from forming pain, deformities, lytic changes and osteopenia persist or take years of therapy to improve.

Despite GCase treatment adult patients remain at risk for pathological bone fractures.

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