Gaucher disease (GD) results from a deficiency in the lysosomal hydrolase beta-glucosidase (glucocerebrosidase).
- Encoded by the glucocerebrosidase 1 (GBA1) gene located on chromosome 1q21-q31.
- Autosomal recessive
- There are > 400 distinct mutations; 6 mutations are very common among the Ashkenazi Jewish population.
GD is classified into 3 types:
- Type 1: Non-neuronopathic
- Type 2: Acute neuronopathic form
- Type 3: Chronic or subacute neuronopathic form, further classified as:
- Type 3a
- Type 3b
- Type 3c
- Type 1
- Most common, 90% of GD cases
- 1 in 40,000–50,000 live births in the general population
- More common in the Ashkenazi Jewish population:
- Most prevalent inherited disorder among the Ashkenazi Jewish
- Carrier frequency: 6%
- Type 2
- Incidence: 1 in 150,000 in the general population
- No ethnic predilection
- Rare in the Ashkenazi Jewish population
- Type 3
- Incidence: 1 in 200,000 in the general population
- Accounts for 5% of all patients with GD
- More common in:
- Northern Europe
- East Asia
A deficiency in glucocerebrosidase results in the accumulation of glucocerebroside in reticuloendothelial system cells, which results in:
- Infiltration of the bone marrow → ↓ hematopoiesis → cytopenias
- ↓ Bone density
- Enlargement of the liver and spleen
- Accumulation of lipid-laden macrophages in the perivascular spaces of the brain
GD is a multisystemic lipidosis with a variable clinical presentation.
- Time course:
- Variable age at onset, can present at any stage of life
- Some asymptomatic throughout life
- Median age at diagnosis: 40 years
- Signs and symptoms:
- Bruising from thrombocytopenia
- Chronic fatigue secondary to anemia
- Bone pain
- Avascular necrosis of the femur
- Pathologic fractures
- Interstitial lung disease
- Pulmonary hypertension
- Time course:
- Present before 9 months of age
- May present at birth or infancy
- Death early in life:
- Often by 2 years of age
- Frequently caused by aspiration or respiratory failure
- Signs and symptoms:
- Rapid neurodegenerative course
- Failure to thrive
- Feeding difficulty
- ↑ Muscle tone
- Stridor due to laryngeal spasm
- Oculomotor apraxia
- Time course:
- Can present by age 2, often in the 1st decade of life
- Gradual onset of symptoms
- Death occurs within a few years without treatment.
- May survive into adulthood
- Signs and symptoms:
- Progressive encephalopathy
- Slowing of saccadic eye movements
- Bone pain and fractures
- Skeletal irregularities
- Distinguishing clinical features of the 3 subtypes:
- Type 3a:
- Dominant neurologic manifestations and mild visceral disease
- Progressive myotonia and dementia
- Type 3b:
- Dominant visceral disease and skeletal abnormalities with mild neurologic signs
- Isolated supranuclear gaze palsy
- Type 3c (cardiovascular form):
- Visceral disease associated with cardiac involvement (cardiovascular calcification)
- Supranuclear gaze palsy
- Corneal opacities
- Type 3a:
Diagnosis and Management
- Clinical suspicion for GD is raised in the presence of organomegaly, easy bruising, bone pain, and failure to thrive.
- Supporting laboratory studies:
- ↑ Liver function tests
- Diagnostic testing:
- Glucocerebrosidase activity in leukocytes (< 15% of normal enzyme activity is diagnostic)
- Bone marrow analysis may show Gaucher cells (no longer the confirmation test of choice):
- Lipid-laden macrophages
- Cytoplasm has a “crinkled tissue paper” appearance.
- Genetic analysis to identify specific mutations provides further confirmation.
Treatment is supportive and focused on improving quality of life. Some patients with GD have mild symptoms and don’t require treatment.
- Enzyme replacement therapy (ERT):
- An option for some patients
- IV administration of glucocerebrosidase
- Does not help with CNS symptoms, as ERT does not cross the blood–brain barrier.
- Substrate reduction therapy:
- Oral administration
- Goal is to ↓ the synthesis of glucocerebroside → ↓ glycolipid accumulation.
- Bone marrow transplantation (BMT):
- Considered a last resort for severe GD
- ↑ Morbidity and mortality
- Provides a definitive cure
- Niemann-Pick disease type A (NPD-A): a lysosomal storage disorder caused by an acid sphingomyelinase enzyme deficiency. The disease is characterized by progressive neurodegeneration starting within a few months of life and resulting in death by age 3. Clinical manifestations include a macular cherry-red spot, difficulty feeding, loss of motor skills, hypotonia, and organomegaly. Diagnosis includes measurement of sphingomyelinase enzyme activity and genetic testing. Management is supportive.
- Tay-Sachs disease: an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot upon physical examination. Diagnosis is made with enzyme activity testing and molecular analysis. Management is supportive.
- Sandhoff disease (SD): a lysosomal storage disorder caused by a deficiency in both HEXA and HEXB. Juvenile SD is characterized by progressive neurodegeneration starting at 6 months of age. Clinical manifestations include hyperacusis, a macular cherry-red spot, blindness, and seizures. Diagnosis is made by measurement of HEXA and HEXB, as well as genetic analysis. Management is supportive.
- Pompe disease (glycogen storage disease II): a lysosomal and glycogen storage disorder caused by acid alpha glucosidase (GAA) deficiency. There are 3 types, with variable onset and presentations. Clinical manifestations include failure to thrive, feeding difficulty, hypotonia, progressive muscle weakness, hypertrophic cardiomyopathy, and respiratory failure. The diagnosis is made with measuring enzyme activity and molecular gene analysis. Management includes supportive measures and enzyme replacement.
- Fabry disease: a lysosomal storage disorder caused by alpha-galactosidase A (GLA) deficiency. This results in glycophospholipid deposition in the vascular endothelium and smooth muscle cells. Clinical manifestations include paresthesias involving the hands and feet, purplish skin lesions (angiokeratomas), decreased sweating, cardiovascular complications, and renal disease. Diagnosis is made with measurement of GLA enzyme activity. Management includes supportive measures and enzyme replacement.
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