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Introduction
  • Autosomal recessive deficiency in B-glucocerebrosidase 
  • Epidemiology
    • incidence
      • most common lysosomal storage disase
      • incidence of ~1 in 40,000 people in general population
    • demographics
      • more common in Ashkenazi Jewish origin 
  • Pathophysiology
    • cell biology
      • enzyme deficency leads to disturbances in cell metabolism with accumulation of sphingolipids in the
        • liver
        • spleen
        • bone marrow
  • Genetics
    • inheritance pattern
      • autosomal recessive
    • classification
      • Type 1 (B-glucocerebrosidase deficency) is most common
      • Type 2
      • Type 3 (with CNS involvement)
Classification
 
 Classification
Type
Clinical Features
Prognosis
Type 1
(Adult Type)
 • Easy bruising
 • Anemia, fractures
 • Treatable with enzyme replacement therapy (fatal if enzyme substitute is not given)
Type 2
(InfantileType)
 • Lethal by age 3
 • Brain and organ involvement
 • Untreatable and lethal during infancy
Type 3
(JuvenileType)
 • Onset in teen years
 • Thrombocytopenia, anemia, enlarged liver
 • Fractures
 • Gradual brain involvement
 • Type 3 is clinically diverse.  
 • The non-CNS effects respond well to enzyme replacement therapy

 
Presentation
  • Symptoms (will depend on the type of Gaucher's disease)
    • Systemic Manifestations
      • fatigue (anemia)
      • prolonged bleeding (thrombocytopenia)
      • fever, chills, sweats (infection)
      • seizure, developmental delay (CNS involvement)
    • Orthopaedic Manifestations
      • bone pain (fracture, osteomyelitis)
      • joint pain or contracture
      • bone crisis (osteonecrosis)
  • Physical exam 
    • inspection
      • abnormal skin and bruising
    • palpation
      • hepatosplenomegaly
    • auscultation
      • cardiac mumur 
    • musculoskeletal
      • bone deformities (80% of patients with Gaucher will develop deformities of the distal femur or proximal tibia)
      • joint contractures
      • pathologic fractures
Evaluation
  • Labs
    • Full blood count
      • anemia and thrombocytopenia are common
    • diagnosis confirmed by elevated plasma levels of glucocerebrosides
  • Histology
    • bone marrow aspirate shows a giant binucleate storage cell filled with glucocerebrosides
      • which accumulate because of an hereditary deficiency of Beta-glucocerebrosidase
  • Imaging
    • radiographs 
      • chest
        • may reveal cardiac involvement (e.g. cardiac enlargement, etc)
      • skeletal 
        • may reveal pathologic fractures, osteonecrosis, abnormal bone remodeling or joint deformity
        • almost all patients have diffuse osteopenia
    • CT/MRI
      • visceral 
        • abdomen may reveal organomegaly
      • skeletal 
        • increased prevalence of osteomyelitis in patients with Gaucher's disease
        • chronic vascular insults may lead to osteonecrosis in the proximal and distal femur, proximal tibia and proximal humerus most commonly
Treatment
  • Nonoperative
    • observation and supportive therapy
      • indications
        • unaffected patients (e.g., no blood result irregularities, minimal organ enlargement, no bony lesions on MRI)
      • modalities
        • extended multidisciplinary approach is essential 
    • enzyme replacement therapy
      • indications
        • all children and symptomatic patients 
        • not effective in Type 2 Gaucher's disease
      • modalities
        • imiglucerase
        • velaglucerase alfa
        • taliglucerase alfa
    • substrate reduction therapy
      • indications
        • less severely affected patients that cannot tolerate IV replacement therapy
      • modalities
        • miglustat
  • Operative
    • bone marrow transplant
      • if performed early may be curative
Complications
  • Fracture management
    • preoperative optimization with enzyme therapy is critical
    • availability of additional blood, clotting factors and platelets due to increased bleeding risk
    • anesthisologist to maintain oxygenation to avoid precipitating bone crisis
    • increased risk of infection
 

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Questions (1)

(OBQ05.80) Absence of the enzyme glucocerebrosidase leads to what clinical entity? Review Topic

QID: 966
1

Niemann-Pick disease

5%

(32/660)

2

Fabry disease

2%

(10/660)

3

Gaucher's disease

83%

(546/660)

4

Tay-Sachs

9%

(57/660)

5

Krabbe disease

2%

(13/660)

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