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

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)
  • Clinical
    • Leukemia
    • Lymphoma (see Lymphoma, [[Lymphoma]])
    • Multiple Myeloma (see Multiple Myeloma, [[Multiple Myeloma]])
• Splenomegaly (see Splenomegaly, [[Splenomegaly]])
  • Epidemiology: most common presenting manifestation
• Splenic Infarction
  • Epidemiology: occurs rarely
  • Clinical
    • Abdominal Pain (see Abdominal Pain, [[Abdominal Pain]])

Neurologic Manifestations

• Parkinson’s Disease (see Parkinson’s Disease, [[Parkinsons Disease]])
• Peripheral Polyneuropathy (see Peripheral Neuropathy, [[Peripheral Neuropathy]])
  • Physiology: non-neuronopathic

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
    • Platypnea/Orthodeoxia (see Platypnea-Orthodeoxia, [[Platypnea-Orthodeoxia]])
• 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
  • Clinical
    • Vertebral Compression Fracture (see Vertebral Compression Fracture, [[Vertebral Compression 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

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