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.