Gaucher disease Flashcards
N370S
presence of this mutation (either 1 copy or 2) indicates lack of primary neurologic involvement–>type 1 Gaucher –> increased risk of Parkinson Disease
homozygous –> avg age of onset is 30
This genotype is the most common in the US and Israel
Outisde the US, more severe phenotypes are more common
Type 1 Gaucher Disease Overview
Non-neuronopathic - lack of primary CNS involvement
accounts for 94% of cases
Highly variable clinical expression
When it manifests in childhood, it can be progressive, multisystemic, and debilitating
Type 1 Gaucher disease symptoms
Can present with any of the following:
- bone pain
- bone crisis
- hepatomegaly
- splenomegaly (most common)
- anemia
- thrombocytopenia
- ehrlenmeyer flask deformity
- pathologic fracture
- joint pain
- osteopenia
- osteonecrosis
- bone marrow infiltration
some symptoms may be severe, and others completely silent
Type 1 Gaucher disease
- age of onset
- pediatric presentation
Can manifest at any age, but most commonly in 1st or 2nd decade of life
Children with GD1 have splenomegaly, easy bruising/bleeding/hypermenorrhagia, and most importantly: slower than normal growth and pubertal development
Type 2 Gaucher disease
Acute neuronopathic Onset in infancy Most severe type; neurologic disease Early death - includes hydrops fetalis, congenital icthyosis, progressive neurologic involvement Panethnic Little or no GBA activity - null alleles
Type 3 Gaucher disease
Often misdiagnosed as type 1
Chronic neuronopathy
Childhood onset with survival to 2nd to 4th decade
Somatic signs, such as hepatosplenomegaly and bone deformity may precede neurologic symptoms by many years
Characteristic: oculomotor apraxia, bulbar signs
Seizures in childhood or early adulthood
Cardiac calcification
Hydrocephalus
Diagnosis of Gaucher disease (type 1)
enzyme assay: glucocerebrosidase activity (gold standard)
GBA testing/mutation analysis
–> issue: pseudogene
Bone marrow biopsy to detect Gaucher cells, which accumulate and also release toxic cytokines
Gaucher disease biomarkers
Interpreted in conjunction with clinical assessments
consistent, serial monitoring of 1 or more
Chitotriosidase
- most sensitive biomarker
- secreted by active macrophages
- issue: activity is absent in 6% of Gaucher patients
- serial increase may be early indicator of clinical relapse
- decreased activity with ERT
Lyso GL-1
- greater utility with interpreting residual GD activity
- key biomarker!
- decreased levels with ERT
Gaucher disease-related bone disease
- 90% of Gaucher patients
- main cause of morbidity and reduced quality of life in GD patients
- MRI reveals “dark marrow” affected by Gaucher cell infiltration
- DXA reveals low bone mineral density
- can result in irreversible skeletal complications such as osteonecrosis, joint collapse, pathologic fractures
Indications for treatment of Gaucher disease
anemia
thrombocytopenia
splenomegaly
bone disease
Also consider age, initial assessment, severity and progression of disease
*not all patients will require treatment
Gaucher disease enzyme replacement therapy
available since 1991, gold standard of treatment
Mannose-6-P for lysosomal targeting
Highly effective in increasing hemoglobin and platelet count, decreasing spleen and liver volume
Improved bone density
Best option for GD type 1
Gaucher disease substrate reduction therapy
Oral treatment
Zavesca - miglustat
- approved when ERT not possible
- some adverse effects
Eliglustat - ceramide-based inhibitor, results in decreased production of glucosylceramide
NOT approved for:
- ultra rapid metabolizers (CYP2D6 screening prior to treatment)
- pregnant or lactating women
Association between GD and Parkinsons disease
Both homozygote and heterozygote carriers of GBA at increased risk
GBA mutation is the most common genetic risk factor
Avg age of onset for GD patients: 54 years
