Gaucher Disease

 

Most common sphingolipidosis (a group of lysosomal storage disorders)

Glucocerebrosidase deficiency

GBA1 Gene mutation

 

Pathophysiology

 

Autosomal recessive inheritance of mutations in the GBA1 gene

Deficiency of glucocerebrosidase leads to accumulation of its substrate, glucosylceramide in macrophages/monocytes à formation of abnormal ‘Gaucher cells’

 

Epidemiology

 

1/800 Ashkenazi Jews

1/40,000-60,000 General population

 

Clinical Features

 

Huge variability - May be asymptomatic throughout life, or present in early childhood

 

Cytopenias, hepatomegaly and massive splenomegaly caused by infiltration with Gaucher cells

Fatigue, growth restriction, delayed puberty, acute bone pains, osteoporosis, avascular necrosis, gallstones, pulmonary hypertension, neurological impairment

 

Splenomegaly, present in 90%, may be the only clinical sign

 

Type 1 (up to 90% of cases) – Mostly effects the viscera. Predisposed to Parkinson’s disease

Type 2 – severe neurological impairment, hydrops fetalis

Type 3 – variable neurological impairment, horizontal ophthalmoplegia

 

Diagnosis

 

Diagnostic:

Enzyme activity – acid glucocerebrosidase activity in leukocytes (10-15% of normal values)

Genetics – genome sequencing (>300 different mutations described)

 

BM aspirate – not indicated for diagnosis of Gaucher, but is often performed due to presenting features of cytopenias / organomegaly and is likely to demonstrate Gaucher cells.

 

Disease biomarkers (response to treatment):

Chitotriosidase levels

CCL18 levels

 

Treatment

 

IV Enzyme Replacement Therapy – imiglucerase, velaglucerase, taliglucerase

PO Inhibitors of glucosylceramide synthesis – miglustat, eliglustat

 

(Pseudo-Gaucher Cells)

 

Caused by histocytic accumulation of immunoglobulin crystals, and seen in myeloma, waldenstroms, CML and MDS.