Pathophysiology

1) metabolic disease due to defect in beta-glucocerebrosidase (beta-glucosidase) Type 1 – 2) adult onset, chronic, highly variable course 3) no defects in eye movement 4) lacks neurological deficits Type 2 – 5) infantile onset, acute course 6) defects in eye movement 7) neurological defects are present Type 3 – 8) childhood to adult onset, highly variable course 9) defects in eye movement 10) late neurological defects

Signs and Symptoms

1) massive hepatomegaly (especially in type 3) 2) splenomegaly 3) bone destruction with aseptic necrosis of femoral head and femoral neck fractures 4) skin pigment changes 5) episodic “bone crisis” with fever, erythema over affected bones, and leukocytosis 6) severe neurologic involvement (types II and III) with seizures and dementia 7) infiltrative lung disease with dyspnea

Characteristic Test Findings

Laboratory – 1) thrombocytopenia 2) anemia 3) increased serum ferritin 4) increased serum ACE levels 5) increased plasma chitotriosidase 6) leuckocytosis Radiology – 7) ground-glass appearance to lung fields 8) bone infarctions seen on nuclear medicine scans 9) flaring of diaphysis and metaphysis

Histology/Gross Pathology

1) presence of Gaucher’s cells (macrophages with abnormal buildup of glucocerebroside) in liver, spleen, and lung 2) increased osteoclasts in bone 3) decreased mineral density of bone

Biochemistry

1) Beta-glucosidase catalyzes cleavage of glucocerbroside to glucoceramide 2) if this enzyme is missing, glucocerebroside (glucosylceramide) accumulates in macrophages 3) types I and III have some residual enzyme activity

Inheritance/Epidemiology

1) most common lysosomal storage disease 2) occurs in 1/60,000 births overall; in 1/900 births in Ashkenazi Jews (type 1) 3) gene defect is at 1q21 4) type III is most common in people of Swedish descent 5) autosomal recessive

Treatment

1) enzyme replacement therapy with beta-glucosidase (this reduces hepatosplenomegaly over 1 year and reduces bone lesions over 3-4 years; the neurologic deficits do not reverse) 2) some patients benefit from splenectomy 3) gene therapy trials are underway 4) joint replacement as needed

Tips for USMLE

1) if Gaucher’s cells are mentioned, obviously it is Gaucher’s disease 2) if macrophages filled with glucocerebroside are mentioned, think Gaucher’s 3) if bone crisis is mentioned, think Gauchers.