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Gaucher's disease
Classification and external resources
ICD-10 E75.2 (ILDS E75. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings E00-E35 - Endocrine diseases (E00-E07 Thyroid gland / Thyroid hormone ( Congenital iodine-deficiency syndrome ( The International League of Dermatological Societies (ILDS is a Non-governmental organization affiliated with the World Health Organization. 220)
ICD-9 272.7
OMIM 230800 230900 231000
DiseasesDB 5124
MedlinePlus 000564
eMedicine ped/837  derm/709
MeSH D005776

Gaucher's disease (IPA: [goʃez dəsiːz]) is the most common of the lysosomal storage diseases. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. MedlinePlus, with the MedlinePlus Medical Encyclopedia, is a website network containing Health information from the world's largest medical Library eMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely two medical doctors Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books The lysosomal storage diseases are a group of over forty human Genetic disorders that result from defects in lysosomal function It is caused by a deficiency of the enzyme glucocerebrosidase, leading to an accumulation of its substrate, the fatty substance glucocerebroside (also known as glucosylceramide). Glucocerebrosidase (also called glucosylceramidase β-glucosidase or D-glucosyl-N-acylsphingosine glucohydrolase is an Enzyme ( that is needed to cleave by Hydrolysis Cerebrosides are Glycosphingolipids which are important components in animal Muscle and Nerve Cell membranes Myelin is the most well Glucocerebroside (also called glucosylceramide) is any of the Cerebrosides in which the Monosaccharide head group is Glucose. Fatty material can collect in the spleen, liver, kidneys, lungs, brain and bone marrow. The spleen is an organ found in all Vertebrate animals In humans the spleen is located in the abdomen of the body where it functions in the destruction of redundant Red The kidneys are complicated organs that have numerous biological roles lung is the essential Respiration organ in air-breathing Animals including most Tetrapods a few Fish and a few Snails The most primitive The brain is the center of the Nervous system in animals All Vertebrates and the majority of Invertebrates have a brain Symptoms may include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may cause pain, severe neurologic complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelets and yellow fatty deposits on the sclera. This is a list of skeletal disorders, these affect the development and structure of the Skeletal system Bone cyst Bone spur (Osteophytes A Lymph node ( lɪmf noʊd is an organ consisting of many types of cells and is a part of the Lymphatic system. Anemia ( AmE) or anæmia/anaemia ( BrE) (from the Ancient Greek grc-Latn anaîmia, meaning “without blood” is defined as a qualitative Platelets, or Thrombocytes, are small cytoplasmic bodies derived from cells They circulate in the Blood of Mammals and are involved The sclera, called the white or white of the eye, is the opaque (usually white though certain animals such as horses and lizards can have black sclera fibrous Persons affected most seriously may also be more susceptible to infection. The disease shows autosomal recessive inheritance and therefore affects both males and females. It is named after the French doctor Philippe Gaucher who originally described it in 1882. Philippe Charles Ernest Gaucher ( July 26, 1854 – January 25, 1918) was a French Dermatologist who was born in the department

Contents

Subtypes

Gaucher's disease has three common clinical subtypes.

These subtypes have come under some criticism for not taking account of the spectrum of phenotypes. A phenotype is any observable characteristic of an Organism, such as its morphology, Development, biochemical or physiological properties [1] There are also compound heterozygous variations which considerably increase the complexity of predicting disease course.

Signs and symptoms

Diagnosis

In populations with high rates of carriage (Ashkenazi Jews and Norrbottnian Swedes and a few African tribes), some family members of the index patient may already have been diagnosed with Gaucher's. An Erlenmeyer flask, commonly known as a conical flask or E-flask, is a widely used type of Laboratory flask which features a conical base and a cylindrical The femur is the thigh bone In Humans, it is the longest, most voluminous and strongest Bone. For the drug referred to as "pigment" see Black tar heroin. Ashkenazi Jews, also known as Ashkenazic Jews or Ashkenazim ( Hebrew: אַשְׁכֲּנָזִים, ˌaʃkəˈnazim sing Norrbotten (English meaning Northbottom) is a Swedish province ( landskap) in northernmost Sweden. Truly sporadic cases may suffer diagnostic delay due to the protean symptoms.

Biochemical abnormalities: high alkaline phosphatase, angiotensin-converting enzyme (ACE) and immunoglobulin levels. Alkaline phosphatase ( ALP) ( is a Hydrolase Enzyme responsible for removing Phosphate groups from many types of molecules including Angiotensin I converting enzyme ( ACE,) is an Exopeptidase. Functions It has two primary functions it catalyses the conversion of Antibodies (also known as immunoglobulins, abbreviated Ig) are Gamma globulin Proteins that are found in Blood or other Bodily

The diagnosis is made with genetic testing of the β-glucosidase gene. Genetic testing allows the genetic Diagnosis of vulnerabilities to inherited Diseases, and can also be used to determine a person's Ancestry. As there are numerous different mutations, sequencing of the gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available, and is useful when there is a known genetic risk factor.

Histological findings of cells containing "crinkled paper" cytoplasm and glycolipid-laden macrophages.

Pathophysiology

Acid β-glucosidase
Acid β-glucosidase

The disease is caused by a defect in the housekeeping gene lysosomal gluco-cerebrosidase (also known as β-glucosidase, EC 3.2.1.45, PDB 1OGS) on the first chromosome (1q21). Gene expression is the process by which inheritable information from a Gene, such as the DNA sequence, is made into a functional Gene product, such This article is about the Enzyme Commission codes For the European Commission system for coding chemicals see EC-No. The Protein Data Bank ( PDB) is a repository for 3-D structural data of Proteins and Nucleic acids These data typically obtained by X-ray crystallography A chromosome is an organized structure of DNA and Protein that is found in cells. The enzyme is a 55. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins 6 KD, 497 amino acids long protein that catalyses the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. The unified atomic mass unit ( u) or Dalton ( Da) or sometimes universal mass unit, is an unit of Mass used to express In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this Glucocerebroside (also called glucosylceramide) is any of the Cerebrosides in which the Monosaccharide head group is Glucose. The cell membrane (also called the plasma membrane, plasmalemma, or "phospholipid bilayer" is a Selectively permeable Lipid bilayer The macrophages that clear these cells are unable to eliminate the waste product, which accumulates in fibrils, and turn into Gaucher cells, which appear on light microscopy as appearing to contain crumpled-up paper. Macrophages ( Greek: "big eaters" from makros "large" + phagein "eat" ( Mø) are cells within the tissues that Microscopy is the technical field of using microscopes to view samples or objects

Different mutations in the β-glucosidase determine the remaining activity of the enzyme, and, to a large extent, the phenotype. A phenotype is any observable characteristic of an Organism, such as its morphology, Development, biochemical or physiological properties

In the brain (type II and III), glucocerebroside accumulates due to the turnover of complex lipids during brain development and the formation of the myelin sheath of nerves. Lipids are broadly defined as any fat- Soluble ( lipophilic) naturally-occurring Molecule, such as fats oils waxes cholesterol sterols fat-soluble Myelin is an electrically-insulating Dielectric Phospholipid layer that surrounds only the Axons of many Neurons It is an outgrowth

Research suggests that heterozygotes for particular acid β-glucosidase mutations are at an increased risk of Parkinson's disease. Parkinson's disease (also known as Parkinson disease or PD) is a degenerative disorder of the Central nervous system that often impairs the sufferer's [1] A study of 1525 Gaucher patients in the United States suggested that while cancer risk is not elevated, particular malignancies (non-Hodgkin lymphoma, melanoma and pancreatic cancer) occurred at a 2-3 times higher rate. The United States of America —commonly referred to as the The non-Hodgkin lymphomas are a diverse group of hematologic cancers which encompass any Lymphoma other than Hodgkin lymphoma. Melanoma is a Malignant Tumor of Melanocytes which are found predominantly in skin but also in the Bowel and the Eye (see Pancreatic cancer is a malignant tumor of the Pancreas. Each year about 37680 individuals in the United States are diagnosed with this condition and 34290 [2]

Classification and genetics

The three types of Gaucher's disease are inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of mutations. Genetic counseling is the process by which patients or relatives at risk of an inherited disorder are advised of the consequences and nature of the disorder the probability of developing Genetic testing allows the genetic Diagnosis of vulnerabilities to inherited Diseases, and can also be used to determine a person's Ancestry.

Each type has been linked to particular mutations. In all, there are about 80 known mutations, grouped into three main types:[3]

Diaz et al suggest that the Gaucher-causing mutations entered the Ashkenazi Jewish gene pool in the early Middle Ages (48-55 generations ago). [4]

Epidemiology

Treatment

For type 1 and most type 3 patients, enzyme replacement treatment with mannose-terminated recombinant glucocerebrosidase, 60 Units/kg, given intravenously every two weeks can dramatically decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations. Enzyme replacement therapy is a medical treatment replacing an Enzyme in patients in whom that particular enzyme is deficient or absent Recombinant DNA is a form of synthetic DNA that is engineered through the combination or insertion of one or more DNA strands thereby combining DNA sequences Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. The liver is a vital organ in the human body and is present in Vertebrates and some other animals The spleen is an organ found in all Vertebrate animals In humans the spleen is located in the abdomen of the body where it functions in the destruction of redundant Red This treatment is becoming the standard in treating Gaucher's. Due to the low incidence, this has become an orphan drug in many countries. In the US, an orphan drug is any drug developed under the Orphan Drug Act of January 1983 ("ODA" a Federal law concerning Rare diseases Successful bone marrow transplantation cures the non-neurological manifestations of the disease, because it introduces a monocyte population with active β-glucosidase. Monocyte is a type of Leukocyte, part of the Human body 's Immune system. However, this procedure carries significant risk and is rarely performed in Gaucher patients. Surgery to remove the spleen (splenectomy) may be required on rare occasions if the patient is anemic or when the enlarged organ affects the patient’s comfort. A splenectomy is a procedure that involves the removal of the Spleen by operative means Blood transfusion may benefit some anemic patients. Blood transfusion is the process of transferring Blood or blood-based products from one person into the Circulatory system of another Other patients may require joint replacement surgery to improve mobility and quality of life. Joint replacement is one of the most common and successful operations in modern Orthopaedic surgery. Other treatment options include antibiotics for infections, antiepileptics for seizures, bisphosphonates for bone lesions, and liver transplants. In modern usage an antibiotic is a Chemotherapeutic agent with activity against Microorganisms such as Bacteria, fungi or Protozoa An infection is the detrimental Colonization of a host Organism by a foreign Species. The anticonvulsants, also called antiepileptic drugs (abbreviated "AEDs" are a diverse group of pharmaceuticals used in the treatment of epileptic Liver transplantation or hepatic transplantation is the replacement of a diseased Liver with a healthy liver Allograft. Substrate reduction therapy may prove to be effective in stopping Type 2, as it can cross through the blood barrier into the brain. There is currently no effective treatment for the severe brain damage that may occur in patients with types 2 and 3 Gaucher disease. Gene therapy may be a future step. Gene therapy is the insertion of Genes into an individual's cells and tissues to treat a Disease, and Hereditary diseases in which a

Gaucher's disease has recently become a target for more than one effort at pharmacological chaperoning since the crystal structure of glucocerebrosidase is known. A pharmacological chaperone is a relatively new concept in the treatment of certain genetic disease Glucocerebrosidase (also called glucosylceramidase β-glucosidase or D-glucosyl-N-acylsphingosine glucohydrolase is an Enzyme ( that is needed to cleave by Hydrolysis

The currently existing treatment of Gaucher's disease, Cerezyme (imiglucerase for injection), costs up to $550,000 annually for a single patient and the treatment should be continued for life. Imiglucerase is a Recombinant DNA -produced analogue of human β- Glucocerebrosidase. This recombinant β-glucosidase is given intravenously. Miglustat is another drug approved for this disease in 2003. Miglustat is a drug used to treat Gaucher disease. It inhibits the Enzyme Glucosylceramide synthase, an essential enzyme for the synthesis of most

History

Philippe Gaucher described the disease in his doctoral thesis in 1882. Philippe Charles Ernest Gaucher ( July 26, 1854 – January 25, 1918) was a French Dermatologist who was born in the department A dissertation (also called thesis or disquisition) is a document that presents the author's Research and findings and is submitted in support of candidature Year 1882 ( MDCCCLXXXII) was a Common year starting on Sunday (link will display the full calendar of the Gregorian calendar (or a Common [6] The biochemical basis for the disease would be elucidated in 1965 by Brady et al. Year 1965 ( MCMLXV) was a Common year starting on Friday (link will display full calendar of the 1965 Gregorian calendar. [7]

References

  1. ^ Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R (2004). "Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews". N. Engl. J. Med. 351 (19): 1972-7. doi:10.1056/NEJMoa033277. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15525722.  
  2. ^ Landgren O, Turesson I, Gridley G, Caporaso NE (2007). "Risk of Malignant Disease Among 1525 Adult Male US Veterans With Gaucher Disease" 167 (11): 1189-1194. doi:10.1001/archinte.167.11.1189. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17563029.  
  3. ^ Online 'Mendelian Inheritance in Man' (OMIM) 606463
  4. ^ Diaz GA, Gelb BD, Risch N, et al (2000). The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them "Gaucher disease: the origins of the Ashkenazi Jewish N370S and 84GG acid beta-glucosidase mutations". Am. J. Hum. Genet. 66 (6): 1821-32. doi:10.1086/302946. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 10777718.  
  5. ^ National Gaucher Foundation. Retrieved on 2007-05-30. Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. Events 1416 - The Council of Constance, called by the Emperor Sigismund a supporter of Antipope John XXIII burns Jerome of Prague following
  6. ^ Gaucher PCE. De l'epithelioma primitif de la rate, hypertrophie idiopathique de la rate sans leucemie. Academic thesis, Paris, France, 1882.
  7. ^ Brady RO, Kanfer JN, Shapiro D (1965). "Metabolism of glucocerebrosides. II. Evidence of an enzymatic deficiency in Gaucher's disease". Biochem. Biophys. Res. Commun. 18: 221-5. doi:10.1016/0006-291X(65)90743-6. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 14282020.  

External links

The National Institute of Neurological Disorders and Stroke is a part of the U
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