Gaucher Disease

Epidemiology

  • Incidence: occurs in 1 in 75k births worldwide
    • Increased incidence in Ashkenazi Jews

Physiology

  • Autosomal Recessive Lysosomal Storage Disease: beta-glucocerebrosidase (lysosomal B glucosidase) deficiency with deposition of glucocerebrocides (glucosylceramide) in macrophages (Gaucher cells), with accumulation of cells in spleen/liver/bone marrow/CNS/lymph nodes/lung (interstitium and alveoli)
    • Hypersplenism
    • Gaucher Cell: reticulendothelial cell with foamy cytoplasm
    • Pulmonary Hypertension: due to capillary occlusion by glucocerebroside-filled alveolar macrophages, interstitial lung disease, chronic hypoxemia, and splenectomy

Diagnosis

Glucocerebrosidase Activity in Peripheral Leukocytes (see xxxxx, [[xxxx]]): decreased

  • Diagnostic
  • Assay for Glucocerebrosidase Activity in Can Also Be Performed in Cultured Skin Fibroblasts or Other Nucleated Cells

Mutation Analysis

  • Targeted DNA Analysis to Detect the Most Common Mutations

Clinical Manifestations

Perinatal-Lethal Form

  • General Comments
    • Lethal in Utero or in Newborn Period
  • Non-Immune Hydrops Fetalis

Type 1 (GD1)

General Comments

  • Variable Clinical Presentation and Disease Progression
    • Even Among Siblings with the Same Genotype and in Monozygotic Twins
    • May Present in Childhood-Adulthood
  • Most Common Clinical Varient: accounts for 90% of Gaucher disease cases
  • Lifespan: shortened-normal

Endocrinologic Manifestations

  • Delayed Puberty: in children
  • Elevated Basal Metabolic Rate
  • Growth Retardation: in children
  • Insulin Resistance
  • Lipid Abnormalities

Gastrointestinal Manifestations

  • Hepatomegaly (see Hepatomegaly, [[Hepatomegaly]])
    • Epidemiology: occurs in all cases
    • Clinical
      • Liver is Usually 2-3x the Normal Liver Size
      • Hepatic Fibrosis (see Hepatic Fibrosis, [[Hepatic Fibrosis]]): common (although cirrhosis and portal hypertension are uncommon)

Hematologic Manifestations

  • Bone Marrow Infiltration (see Myelofibrosis-Myelophthisis, [[Myelofibrosis-Myelophthisis]])
    • Physiology: myelophthisic process with marrow replacement
    • Diagnosis
      • Bone Marrow Biopsy (see Bone Marrow Biopsy, [[Bone Marrow Biopsy]])
        • Gaucher Cell: foamy cytoplasm
        • Occasional Fibrosis
    • Clinical
      • Anemia (see Anemia, [[Anemia]])
      • Leukopenia (see Leukopenia, [[Leukopenia]]): rarely occurs
      • Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]]): moderate-severe
  • Increased Risk of Malignancy (Predominantly Hematologic)
  • Splenomegaly (see Splenomegaly, [[Splenomegaly]])
    • Epidemiology: most common presenting manifestation
  • Splenic Infarction
    • Epidemiology: occurs rarely
    • Clinical

Neurologic Manifestations

Pulmonary Manifestations

  • Hepatopulmonary Syndrome (see Hepatopulmonary Syndrome, [[Hepatopulmonary Syndrome]])
    • Epidemiology
      • Rare Complication of Gaucher Disease
      • Usually Occurs in Splenectomized Patients with Severe Clinical Disease
    • Physiology: intrapulmonary shunting
    • Clinical
  • Interstitial Lung Disease (ILD) (see Interstitial Lung Disease, [[Interstitial Lung Disease]])
    • Epidemiology:
    • Physiology
      • Gaucher Cell Infiltration of Alveolar Spaces and Interstitium
      • Gaucher Cell Infiltration of Pulmonary Capillaries: may contribute to the development of pulmonary hypertension
      • Mediator-Associated Remodeling of Pulmonary Vasculature: may contribute to the development of pulmonary hypertension
    • Diagnosis
      • Serum Angiotensin Converting Enzyme (ACE) (see Serum Angiotensin Converting Enzyme, [[Serum Angiotensin Converting Enzyme]]): may be elevated
      • Chest X-Ray (CXR)/Chest CT (see Chest X-Ray, [[Chest X-Ray]] and Chest Computed Tomography, [[Chest Computed Tomography]])
        • Interstitial Lung Disease: appears as micronodules, which first appear during first 3 decades of life
        • Mediastinal Lymphadenopathy (see Mediastinal Mass, [[Mediastinal Mass]])
      • Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])
        • Restrictive Pattern
      • Video-Assisted Thoracoscopic Surgery (VATS) with Lung Biopsy (see Video-Assisted Thoracoscopic Surgery, [[Video-Assisted Thoracoscopic Surgery]])
        • Masses of Foamy Alveolar Macrophages (Filled with Glucocerebroside)
        • Absence of Inflammatory Cells and Interstitial Fibrosis
        • Desquamative Interstitial Pneumonia (DIP) (see Desquamative Interstitial Pneumonia, [[Desquamative Interstitial Pneumonia]]): may be seen
    • Clinical
  • Pulmonary Hypertension (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
    • Epidemiology: only one reported case of pulmonary hypertension

Rheumatologic Manifestations

  • General Comments
    • Bone Pain/Bone Crises/Severe Bone Disease are More Common in Asplenic Patients
  • Avascular Necrosis (see Avascular Necrosis, [[Avascular Necrosis]])
    • Clinical: affects proximal/distal femur, proximal tibia, and proximal humerus
  • Diffuse Bone Pain
    • Diagnosis
      • Serum Acid Phosphatase (see Serum Acid Phosphatase, [[Serum Acid Phosphatase]]): elevated
      • X-Rays
        • Long Bone Erosions
        • Erlenmeyer Flask Deformity of Distal Femur
  • Growth Retardation: in children
  • Osteolytic Lesions (see Osteolytic Bone Lesions, [[Osteolytic Bone Lesions]])
  • Pathologic Fracture

Type 2 (GD2)

General Comments

  • Acute Neuronopathic Variant of Gaucher Disease
    • Early Onset: typically in the first year of life
  • Lifespan: death before 2 y/o

Dermatologic Manifestations

  • Congenital Ichthyosis (“Collodion Baby”)

Neurologic Manifestations

  • Arching (Opisthotonos) (see Opisthotonos, [[Opisthotonos]])
  • Oculomotor Dysfunction
    • Clinical
      • Bulbar Paresis/Palsy
      • Saccadic Eye Movement Initiation Abnormalities
      • Strabismus (see Strabismus, [[Strabismus]])
  • Rigidity
  • Seizures (see Seizures, [[Seizures]])
  • Severe Hypertonia
  • Swallowing Dysfunction (see Dysphagia, [[Dysphagia]])

Type 3 (GD3)

General Comments

  • Subacute/Chronic Neuronopathic Variant of Gaucher Disease

Type 3a

  • General Comments
    • Lifespan: 20-30 y/o
  • Ataxia (see Ataxia, [[Ataxia]])
  • Mild Hepatosplenomegaly (see Hepatomegaly, [[Hepatomegaly]] and Splenomegaly, [[Splenomegaly]])
  • Myoclonus (see Myoclonus, [[Myoclonus]])
    • Myoclonic Seizures (see Myoclonus, [[Myoclonus]]): earlier onset
  • Progressive Dementia (see Dementia, [[Dementia]])
  • Strabismus (see Strabismus, [[Strabismus]]): earlier onset
  • Supranuclear Gaze Palsy: earlier onset

Type 3b

  • General Comments
    • Lifespan: shortened (death by 3rd-4th decade of life)
  • Decreased Intelligence
  • Massive Hepatosplenomegaly (see Hepatomegaly, [[Hepatomegaly]] and Splenomegaly, [[Splenomegaly]])
  • Myoclonic Seizures (see Myoclonus, [[Myoclonus]]): late onset
  • Progressive Skeletal Abnormalities
    • Barrel Chest
    • Kyphoscoliosis (see Kyphoscoliosis, [[Kyphoscoliosis]])
  • Scanning (Explosive) Speech: later onset
  • Supranuclear Gaze Palsy
    • Saccadic Eye Movement Initiation Failure
    • Compensatory Head Thrusting

Type 3c (Cardiovascular Variant)

  • General Comments
    • Rare Variant
    • Progression is Variable
    • Lifespan: shortened (death by 3rd-4th decade of life)
  • Cardiovascular Calcification
  • Corneal Opacity
  • Mild Splenomegaly
  • Minimal Bone Disease
  • Minimal Hematologic Disease
  • Supranuclear Gaze Palsy

Treatment

Recombinant Glucocerebrosidase Enzyme Replacement Therapy

  • Indications in Type 1 Disease: Based on Disease Severity or Significant Disease Progression
    • Symptomatic Children
      • Malnutrition
      • Growth Retardation
      • Impaired Psychomotor Development
      • Fatigue
    • Symptomatic Adults
      • Thrombocytopenia <60k
      • Hepatomegaly >2.5x Normal Size
      • Spleen >15x Normal Size
      • Radiologic Evidence of Skeletal Disease
  • Agents
    • Imiglucerase
    • Taliglucerase Alpha
    • Velaglucerase Alfa

Substrate Reduction Therapy

  • Rationale: decreases synthesis of glucocerebroside (substrate of the deficient enzyme), reducing glycolipid accumulation
    • May Be an Alternative in Adult Patients
  • Agents
    • Eliglustat
    • Miglustat (N-Butyldeoxynojirimycin)

Splenectomy (see Splenectomy, [[Splenectomy]])

  • Indications
    • Failure to Control Life-Threatening Thrombocytopenia
    • Unremitting Abdominal Pain Due to Splenic Infarction
    • Severe Restrictive Lung Disease
    • Inferior Vena Cava Syndrome (see Inferior Vena Cava Syndrome, [[Inferior Vena Cava Syndrome]])
    • Inability to Receive Recombinant Glucocerebrosidase Enzyme Replacement Therapy

Hematopoietic Stem Cell Transplantation (HSCT) (see Hematopoietic Stem Cell Transplantation, [[Hematopoietic Stem Cell Transplantation]])

  • Rationale: definitive cure for Gaucher disease
  • Indications
    • Patients at Risk for Neuronopathic Gaucher Disease Who Present Prior to the Onset of Neurologic Manifestations

References

  • Echocardiographic assessment of pulmonary hypertension in Gaucher’s disease. Lancet 1998;351:1544–6
  • The frequency and type of lung involvement in patients with Gaucher’s disease. Lab Invest 1998;58:54A
  • Pulmonary hypertension and Gaucher’s disease: logical association or mere coincidence? Am J Pediatr Hematol Oncol 1990;12:74–6