Gaucher Disease

Question 1

What are the clinical manifestations of Gaucher Type 1?

Answer 1

lung (alveolar macrophages)- infiltrative lung disease
*liver (NOT hepatocytes; Kupffer cells)- hepatomegally
*spleen (tissue macrophages)- massive splenomegally, cytopenia, hypermetabolic state (fatigue)
bone marrow- bone marrow infiltration, cytopenia
bone osteoclasts- chronic bone pain, avascular osteonecrosis, osteoporosis/pathological fractures

Question 2

What causes Gaucher disease?

Answer 2

AR mutations to the GBA gene resulting in deficiency of acid beta glucosidase
results in storage of GL-1 primarily in cells of the monocyte/macrophage lineage

Question 3

What is the clinical spectrum of Gaucher disease?

Answer 3

neuropathic to non-neuropathic

Question 4

What phenotype is associated with the N370S genotype?

Answer 4

Gaucher disease
neuroprotective
AJ
homozygotes present at 30-40 years old (rather than childhood) and have Type I non-neuropathic disease that is mild to severe
N370S/L444P presents as Type I non-neuropathic disease that is moderate to severe
N370S/IVS2+1 or N370S/84GG presents as Type I non-neuropathic that is severe

Question 5

What phenotype is associated with the L444P genotype?

Answer 5

homozygotes present with Type 2 or 3 neuronopathic Gaucher that is severe

Question 6

What phenotype is associated with the D409H genotype?

Answer 6

homozygotes are very rare (mostly in Arab populations) and present with Type 3 neuropathic Gaucher with cardiac involvement

Question 7

Describe the phenotypic continuum of neuropathic Gaucher disease.

Answer 7

Type 3 (less severe)
abnormal horizontal saccodes
secondary neurological development
hydrocephalus, cardica valve calcifications
dementia and seizures
myoclonic epilepsy
progressive neurologic degeneration and bulbar involvement
congenital icthyosis
hydrops fetalis
Type 2 (more severe)

Question 8

Describe Type 2 Gaucher disease.

Answer 8

little to no glucocerebrosidase activity
acute neuronopathic with severe neurological disease and onset in infancy (death by the age of 2)
pan ethnic
most severe cases present with perinatal lethality including hydrops and/or congenital ichtyosis and progressive neuro involvement beginning prenatally

Question 9

Describe Type 3 Gaucher disease.

Answer 9

chronic neuronopathic with childhood onset (survival into the 2nd to 4th decade)
presents with hepatomegally, bone involvement, cardiac calcification, hydrocephaluschronic neurodegeneration, somatic signs may precede neuro by many years with seizures in childhood/early adulthood
neuro signs include oculomotor apraxia and bulbar signs

Question 10

Describe Type 1 Gaucher disease.

Answer 10

most prevalent
non-neuronopathic- lack of primary central nervous system involvement
clinical expression highly variable
presents with multisystem involvement (bone pain/crisis, fatigue, abdominal pain, easy bruising/bleeding, erlenmeyer flask deformity, hepatomegally, splenomegally with decreased appetite, anemia and thrombocytopenia, osteonecrosis, osteopenia, pathologic fracture, joint collapse, and bone marrow infiltration)
children present with delayed growth (short stature), puberty, and menarchy as well as hepatomegally, anemia, thrombocytopenia, osteopenia, bone marrow infiltration, and Erlenmeyer flask deformities

Question 11

How is Gaucher disease diagnosed?

Answer 11

enzyme assay (glucocerebrosidase activity in peripheral blood leucocytes/cultured fibroblasts/dried blood spot) is gold standard
mutation analysis for confirmation (mutations can be in cis)
bone marrow biopsy (not diagnostic)

Question 12

What biomarkers are surrogates of burden of Gaucher disease used to monitor treatment?

Answer 12

chitotriosidase (secreted by macrophages- not present in all patients but sensitive)
angiotensin converting enzyme (ACE- not specific)
tartrate resistant acid phosphatase (TARP)
CLL18 (excreted by active magrophages)
Lyso GL1

Question 13

What lab findings are associated with Gaucher disease?

Answer 13

elevated ferritin, low HDL/LDL, elevated biomarkers, thrombocytopenia and anemia, monoclonal/polyclonal gammopathies, elevated PT/PTT

Question 14

What visceral findings are associated with Gaucher disease?

Answer 14

iron depositions in liver and spleen, gall stones, Gaucher lesions in spleen/liver, increased spleen and liver volume

Question 15

What associated issues need to be considered in patients with Gaucher disease?

Answer 15

bone disease (in 90% of patients; primary cause of morbidity/decreased QOL; osteonecrosis and dark marrow)
pulmonary HTN (increased risk if pt has had splenectomy, check for with baseline doppler ECHO and annually)
increased risk of malignancy (multiple myeloma other hematologic malingancies of B cell and plasma cell mostly)
risk of Parkinson disease (having GBA mutation is single biggest risk but not mendelian; much younger age of onset)
Gallstones
iron overload (fasting ferritan/ transcerrin saturation)

Question 16

What treatments are available for patients with Gaucher disease?

Answer 16

ERT (replaces the amount of enzyme necessary to balance with substrate)
Substrate reduction therapy (selective partial inhibitor of glucosylceramide reduces the substrate to level managable by residual enzymes)
none cross blood brain barrier, so no treatment for neurological symptoms or Parkinson
some people will not need treatment (up to provider to decide based on anemia, thrombocytopenia, splenomegally, and bone disease)

Question 17

What impacts a physician’s decision on what kind of therapy to use in patients with Gaucher disease?

Answer 17

safety
lifestyle
compliance
CYP2D6 status (URM can’t use Eliglustat)
drug interactions (patients always need to update providers on what they take)
pregnancy (ERT approved in pregnancy but not Eliglustat)