Gaucher Disease
intro
2nd most common sphingolipidosis, a group of lysosomal storage disorders (Fabry’s is 1st)
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 —> formation of abnormal ‘Gaucher cells’
Epidemiology
1/800 Ashkenazi Jews (1 in 14 are carriers)
1/40,000-60,000 General population
classification
Type 1
Most common type seen in UK, 90% of cases
Mostly effects the viscera – pulmonary hypertension, cytopenias, organomegaly, skeletal complications, hypermetabolic symptoms.
Predisposed to Parkinson’s disease
Variable life span.
Type 2
Severe neurological impairment, hydrops fetalis
Survival <2yrs
Type 3
Variable neurological impairment, horizontal ophthalmoplegia
Survival <40yrs
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
Erlenmeyer Flask deformity – distal expansion of the long bones (esp. the femur), said to look like the eponymous wide-necked flasks used in laboratories.
Splenomegaly, present in 90%, may be the only clinical sign
Increased risk of haematological malignancy – esp. Myeloma (50x risk) and B-cell lymphoma but others also occur.
Diagnosis
Often delayed diagnosis:
Not infrequently >10 years from onset of symptoms
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
Biochemical Profile:
Clonal gammopathies are common
Similar to HLH – hyperferritinaemia, hypofibrinogenaemia, raised ACE – reflects chronic inflammatory state
Treatment
Enzyme Replacement Therapy – IV recombinant enzymes
Imiglucerase, velaglucerase, taliglucerase
SRT – Substrate Reduction Therapy - PO Inhibitors of glucosylceramide synthesis
Miglustat, now generic
Eliglustat, CYP2D6 metabolism like warfarin. CYP2D6 genotyping used to dose drug!
Gene Therapy Developments
Ex-vivo: Lentivirus in cultured BM cells then transplanted (US)
In-Vivo: AAV directly administered to patient (UK)
In utero therapy also in development
(Pseudo-Gaucher Cells)
Caused by histocytic accumulation of immunoglobulin crystals, and seen in myeloma, waldenstroms, CML and MDS.