Gaucher Disease

Gaucher Disease (GD) is an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancelysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables clinical presentation. Type 1 is non-neuronopathic, whereas types 2 and 3 are neuronopathic. Manifestations can include bruising, lethargy, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, skeletal involvement, and hepatosplenomegaly. Neuropathic types can present with cognitive decline, ataxia, gaze abnormalities, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. Diagnosis is based on clinical suspicion and confirmed by measurement of glucocerebrosidase activity in peripheral blood leukocytes. Genetic analysis can also be used to confirm the diagnosis. Management is supportive and focused on controlling symptoms and improving quality of life. Enzyme replacement therapy, substrate reduction therapy, and bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow transplantation (BMT) are treatment options for some patients.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Etiology

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.

Classification

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

Epidemiology

  • 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
    • Rare
    • 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
      • Egypt
      • East Asia

Pathophysiology

A deficiency in glucocerebrosidase results in the accumulation of glucocerebroside in reticuloendothelial system cells, which results in:

  • Infiltration of the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow → ↓ hematopoiesis → cytopenias
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones density
  • Enlargement of the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen
  • Accumulation of lipid-laden macrophages in the perivascular spaces of the brain
Lysosomal storage pathway for gaucher disease

The lysosomal storage pathway:
Gaucher Disease results from deficiency of glucocerebrosidase (step 3), leading to an accumulation of glucocerebroside.

Image by Lecturio. License: CC BY-NC-SA 4.0

Clinical Presentation

GD is a multisystemic lipidosis with a variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables clinical presentation.

Type 1

  • 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 Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
    • Chronic fatigue secondary to anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • Hepatosplenomegaly
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Avascular necrosis of the femur
    • Pathologic fractures
    • Osteopenia/ osteoporosis Osteoporosis Osteoporosis refers to a decrease in bone mass and density leading to an increased number of fractures. There are 2 forms of osteoporosis: primary, which is commonly postmenopausal or senile; and secondary, which is a manifestation of immobilization, underlying medical disorders, or long-term use of certain medications. Osteoporosis
    • Interstitial lung disease
    • Pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension
A child with massive hepatosplenomegaly due to gaucher disease

A child with massive hepatosplenomegaly due to Gaucher disease

Image: “Dominican child with Gaucher disease” by Estrada-Veras JI, Cabrera-Peña GA, Pérez-Estrella de Ferrán C. License: CC BY 4.0, cropped by Lecturio.

Type 2

  • 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 Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure
  • Signs and symptoms:
    • Rapid neurodegenerative course
    • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive
    • Feeding difficulty
    • Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia
    • ↑ Muscle tone
    • Stridor due to laryngeal spasm
    • Seizures
    • Oculomotor apraxia
    • Strabismus Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus
    • Hepatosplenomegaly
    • Ichthyosis
Neonatal presentations of gaucher disease

Neonatal presentation of Gaucher disease, type 2 subtype: hydrops, peeling, and shiny skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin

Image: “Neonatal presentations of Gaucher disease” by Neonatology Department, Charles Nicolle Hospital, Tunis-El Manar University, Tunis, Tunisia. License: CC BY 2.0

Type 3

  • 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
    • Seizures
    • Slowing of saccadic eye movements
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 
      • Ataxia
    • 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

Diagnosis and Management

Diagnosis

  • Clinical suspicion for GD is raised in the presence of organomegaly, easy bruising, bone pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and failure to thrive. 
  • Supporting laboratory studies: 
    • Pancytopenia
    • Liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests
  • Diagnostic testing:
    • Glucocerebrosidase activity in leukocytes (< 15% of normal enzyme activity is diagnostic)
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones 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.
Bone marrow smear showing gaucher cell

Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones marrow smear showing a Gaucher cell in a patient with type 3 Gaucher disease:
Notice the cytoplasm has a striated, wrinkled appearance.

Image: “ Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones marrow smear showing Gaucher cell” by Mohindroo, S. License: CC BY 2.0

Management

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 Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones marrow transplantation (BMT):
    • Considered a last resort for severe GD
    • ↑ Morbidity and mortality
    • Provides a definitive cure

Differential Diagnosis

  • Niemann-Pick disease Niemann-Pick disease Niemann-Pick disease (NPD) is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic mutation. Type A and type B result from mutations in the SMPD-1 gene, resulting in acid sphingomyelinase enzyme deficiency. Type C results from NPC1 or NPC2 gene mutations, which are needed for intracellular transport of lipids. 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 Tay-Sachs disease Tay-Sachs disease is 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 on physical examination. Tay-Sachs Disease: an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancelysosomal 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 Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. 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 Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables onset and presentations. Clinical manifestations include failure to thrive, feeding difficulty, hypotonia, progressive muscle weakness, hypertrophic cardiomyopathy Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiomyopathy, which is characterized by an asymmetric increase in thickness (hypertrophy) of the left ventricular wall, diastolic dysfunction, and often left ventricular outflow tract obstruction. Hypertrophic Cardiomyopathy, and respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure. The diagnosis is made with measuring enzyme activity and molecular gene analysis. Management includes supportive measures and enzyme replacement.
  • Fabry disease Fabry disease Fabry disease (FD), also known as Anderson-Fabry disease, is an X-linked recessive lysosomal storage disorder and the 2nd most common of the lysosomal storage disorders. Fabry disease is caused by a deficiency in the alpha-galactosidase enzyme (alpha-Gal A), resulting in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in lysosomes. 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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.

References

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  2. Sidransky, E. (2018). Gaucher disease. Medscape. Retrieved July 1, 2021, from https://emedicine.medscape.com/article/944157-overview?src=ppc_google_rlsa-traf_mscp_emed_t1_us
  3. Boer, DEC., et al. (2020). Glucocerebrosidase: Functions in and beyond the lysosome. J Clin Med. 9(3), 736. https://pubmed.ncbi.nlm.nih.gov/32182893/
  4. Winfield, SL, et al. (1997). Identification of three additional genes contiguous to the glucocerebrosidase locus on chromosome 1q21: Implications for Gaucher disease. 7(10), 1020–6. https://pubmed.ncbi.nlm.nih.gov/9331372/
  5. Balwani, M, et al. (2010). Type 1 Gaucher disease: Significant disease manifestations in “asymptomatic” homozygotes identified by prenatal carrier screening. Arch Intern Med. 170(16), 1463–1469. https://pubmed.ncbi.nlm.nih.gov/20837833/
  6. Gomez, G, et al. (2017). GBA mutations in Gaucher type 1 Venezuelan patients: Ethnic origins and frequencies. J Genet. 96(4), 583–589. https://pubmed.ncbi.nlm.nih.gov/28947706/
  7. Bornstein, S, Karpati, M, Peleg, L. (2014). An update of Gaucher mutations distributions in the Ashkenazi Jewish population: Prevalence and country of origin of the mutation R496H. Isr Med Assoc J. 16(11), 683–5. https://pubmed.ncbi.nlm.nih.gov/25558695/
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