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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 Inheritance lysosomal 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 Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor. Type 1 Type 1 Spinal Muscular Atrophy is non-neuronopathic, whereas types 2 and 3 are neuronopathic. Manifestations can include bruising, lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia, 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 and Types, skeletal involvement, and hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus. Neuropathic types can present with cognitive decline, ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia, 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 Leukocytes White blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). White Myeloid Cells: Histology. Genetic analysis can also be used to confirm the diagnosis. Management is supportive and focused on controlling symptoms and improving quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of life. Enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID) therapy, substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes reduction therapy, and bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis transplantation (BMT) are treatment options for some patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship.

Last updated: 24 Jan, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Etiology

Gaucher disease (GD) results from a deficiency in the lysosomal hydrolase Lysosomal hydrolase Overview of Lysosomal Storage Diseases beta-glucosidase (glucocerebrosidase).

  • Encoded by the glucocerebrosidase 1 (GBA1) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics located on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 1q21-q31.
  • 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 Inheritance
  • There are > 400 distinct mutations; 6 mutations are very common among the Ashkenazi Jewish population.

Classification

GD is classified into 3 types:

Epidemiology

  • Type 1 Type 1 Spinal Muscular Atrophy
    • 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 Carrier Vaccination frequency: 6%
  • Type 2 Type 2 Spinal Muscular Atrophy
    • Rare
    • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 in 150,000 in the general population
    • No ethnic predilection
    • Rare in the Ashkenazi Jewish population
  • Type 3 Type 3 Spinal Muscular Atrophy
    • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 in 200,000 in the general population
    • Accounts for 5% of all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with GD
    • More common in:

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 The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis → ↓ hematopoiesis Hematopoiesis The development and formation of various types of blood cells. Hematopoiesis can take place in the bone marrow (medullary) or outside the bone marrow (extramedullary hematopoiesis). Bone Marrow: Composition and Hematopoiesis cytopenias Cytopenias IPEX Syndrome
  • 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. Bones: Structure and Types 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: Anatomy 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: Anatomy
  • Accumulation of lipid-laden macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation in the perivascular spaces of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification
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 Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor.

Type 1 Type 1 Spinal Muscular Atrophy

  • Time course: 
    • 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 age at onset, can present at any stage of life
    • Some asymptomatic throughout life
    • Median Median After arranging the data from loWest to highest, the median is the middle value, separating the lower half from the upper half of the data set. Measures of Central Tendency and Dispersion 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 Chronic Fatigue Fibromyalgia 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 and Types
    • Hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus
    • 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. Bones: Structure and Types pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
    • Avascular Avascular Corneal Abrasions, Erosion, and Ulcers necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage of the femur
    • Pathologic fractures
    • Osteopenia Osteopenia Osteoporosis/ 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 Hepatosplenomegaly Cytomegalovirus 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 Type 2 Spinal Muscular Atrophy

  • 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 Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction
    • Stridor Stridor Laryngomalacia and Tracheomalacia due to laryngeal spasm
    • 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
    • Oculomotor apraxia Apraxia A group of cognitive disorders characterized by the inability to perform previously learned skills that cannot be attributed to deficits of motor or sensory function. The two major subtypes of this condition are ideomotor and ideational apraxia, which refers to loss of the ability to mentally formulate the processes involved with performing an action. For example, dressing apraxia may result from an inability to mentally formulate the act of placing clothes on the body. Apraxias are generally associated with lesions of the dominant parietal lobe and supramarginal gyrus. Cranial Nerve Palsies
    • 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 Hepatosplenomegaly Cytomegalovirus
    • Ichthyosis
Neonatal presentations of gaucher disease

Neonatal presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor of Gaucher disease, type 2 Type 2 Spinal Muscular Atrophy subtype: hydrops Hydrops Cholecystitis, 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. Skin: Structure and Functions

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 Type 3 Spinal Muscular Atrophy

  • 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 Encephalopathy Hyper-IgM Syndrome
    • 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
    • Slowing of saccadic eye movements Saccadic Eye Movements Internuclear Ophthalmoplegia
    • 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. Bones: Structure and Types pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and fractures
    • Skeletal irregularities
  • Distinguishing clinical features of the 3 subtypes:
    • Type 3a:
      • Dominant neurologic manifestations and mild visceral disease
      • Progressive myotonia Myotonia Prolonged failure of muscle relaxation after contraction. This may occur after voluntary contractions, muscle percussion, or electrical stimulation of the muscle. Myotonia is a characteristic feature of myotonic disorders. Ion Channel Myopathy and dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders 
      • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
    • Type 3b:
      • Dominant visceral disease and skeletal abnormalities with mild neurologic signs
      • Isolated supranuclear gaze palsy Palsy paralysis of an area of the body, thus incapable of voluntary movement Cranial Nerve Palsies
    • Type 3c (cardiovascular form):

Diagnosis and Management

Diagnosis

  • Clinical suspicion for GD is raised in the presence of organomegaly, easy bruising Easy bruising Chédiak-Higashi Syndrome, 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. Bones: Structure and Types pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, and 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
  • Supporting laboratory studies: 
    • Pancytopenia Pancytopenia Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. Aplastic Anemia
    • 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: Anatomy function tests
  • Diagnostic testing:
    • Glucocerebrosidase activity in leukocytes Leukocytes White blood cells. These include granular leukocytes (basophils; eosinophils; and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). White Myeloid Cells: Histology (< 15% of normal enzyme activity is diagnostic)
    • Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis analysis may show Gaucher cells (no longer the confirmation test of choice):
      • Lipid-laden macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation
      • Cytoplasm has a “crinkled tissue paper” appearance.
    • Genetic analysis to identify specific mutations provides further confirmation.
Bone marrow smear showing gaucher cell

Bone marrow smear Bone marrow smear Chédiak-Higashi Syndrome showing a Gaucher cell in a patient with type 3 Type 3 Spinal Muscular Atrophy Gaucher disease:
Notice the cytoplasm has a striated, wrinkled appearance.

Image: “ Bone marrow smear Bone marrow smear Chédiak-Higashi Syndrome showing Gaucher cell” by Mohindroo, S. License: CC BY 2.0

Management

Treatment is supportive and focused on improving quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of life. Some patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with GD have mild symptoms and don’t require treatment.

  • Enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID) therapy (ERT):
  • Substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes reduction therapy:
  • Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis transplantation (BMT):

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 Acid sphingomyelinase Niemann-Pick Disease 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 Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology skills, hypotonia Hypotonia Duchenne Muscular Dystrophy, and organomegaly. Diagnosis includes measurement of sphingomyelinase enzyme activity and genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. 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 Inheritance lysosomal storage disorder caused by genetic mutations Genetic Mutations Carcinogenesis in the hexosaminidase A Hexosaminidase A A mammalian beta-hexosaminidase isoform that is a heteromeric protein comprised of both hexosaminidase alpha and hexosaminidase beta subunits. Deficiency of hexosaminidase A due to mutations in the gene encoding the hexosaminidase alpha subunit is a case of Tay-sachs disease. Deficiency of hexosaminidase A and hexosaminidase B due to mutations in the gene encoding the hexosaminidase beta subunit is a case of Sandhoff disease. Tay-Sachs Disease (HEXA) gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity, 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 SD The standard deviation (SD) is a measure of how far each observed value is from the mean in a data set. Measures of Central Tendency and Dispersion): a lysosomal storage disorder caused by a deficiency in both HEXA and HEXB. Juvenile SD SD The standard deviation (SD) is a measure of how far each observed value is from the mean in a data set. Measures of Central Tendency and Dispersion is characterized by progressive neurodegeneration starting at 6 months of age. Clinical manifestations include hyperacusis Hyperacusis An abnormally disproportionate increase in the sensation of loudness in response to auditory stimuli of normal volume. Cochlear disease, vestibulocochlear nerve diseases, facial nerve diseases, stapes surgery, and other disorders may be associated with this condition. Cranial Nerve Palsies, a macular cherry-red spot, blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity, 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 Glycogen storage disease A group of inherited metabolic disorders involving the enzymes responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement. Benign Liver Tumors 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 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, hypotonia Hypotonia Duchenne Muscular Dystrophy, progressive muscle weakness, hypertrophic cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types, 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics analysis. Management includes supportive measures and enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID).
  • 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 Alpha-galactosidase An enzyme that catalyzes the hydrolysis of terminal, non-reducing alpha-d-galactose residues in alpha-galactosides including galactose oligosaccharides, galactomannans, and galactolipids. Fabry Disease A (GLA) deficiency. This results in glycophospholipid deposition in the vascular endothelium Endothelium A layer of epithelium that lines the heart, blood vessels (vascular endothelium), lymph vessels (lymphatic endothelium), and the serous cavities of the body. Arteries: Histology and smooth muscle cells. Clinical manifestations include paresthesias Paresthesias Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. Posterior Cord Syndrome 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. Skin: Structure and Functions 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 Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID).

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/
  8. Aviner, S, et al. (2009). Type 2 Gaucher disease occurs in Ashkenazi Jews but is surprisingly rare. Blood Cells Mol Dis. 43(3), 294–297. https://pubmed.ncbi.nlm.nih.gov/19734074/
  9. National Gaucher Foundation. Gaucher disease. Retrieved July 8, 2021, from https://www.gaucherdisease.org/about-gaucher-disease/what-is/type-2-3/
  10. Dahl, N, Hillborg, PO, Olofsson, A. (1993). Gaucher disease (Norrbottnian type III): Probable founders identified by genealogical and molecular studies. Hum Genet. 92(5), 513–5. https://pubmed.ncbi.nlm.nih.gov/8244344/
  11. Santamaria, F, et al. (1998). Pulmonary manifestations of Gaucher disease: An increased risk for L444P homozygotes? Am J Respir Crit Care Med. 157(3), 677–678. https://pubmed.ncbi.nlm.nih.gov/9517621/
  12. Gaucher Institute. (2021). Introduction. Retrieved July 14, 2021, from https://www.gaucher-institute.com/burden-of-disease/epidemiology-of-gaucher-disease/age-at-disease-onset-and-life-expectancy
  13. NIH Genetic and Rare Diseases Information Center. (2012). Gaucher disease type 3. Retrieved July 14, 2021, from https://rarediseases.info.nih.gov/diseases/2443/gaucher-disease-type-3
  14. Mayo Clinic. (2020). Gaucher disease. Retrieved July 14, 2021, from https://www.mayoclinic.org/diseases-conditions/gauchers-disease/diagnosis-treatment/drc-20355551
  15. Hughes, D, and Sidransky, E. (2019). Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis. In TePas, E. (Ed.), UpToDate. Retrieved July 15, 2021, from https://www.uptodate.com/contents/gaucher-disease-pathogenesis-clinical-manifestations-and-diagnosis
  16. Hughes, D. (2018). Gaucher disease: Treatment. In TePas, E. (Ed.), UpToDate. Retrieved July 15, 2021, from https://www.uptodate.com/contents/gaucher-disease-treatment
  17. Demczko, M. (2020). Gaucher disease. MSD Manual Professional Version. Retrieved July 15, 2021, from https://www.msdmanuals.com/professional/pediatrics/inherited-disorders-of-metabolism/gaucher-disease

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