Gaucher's disease
Encyclopedia
Gaucher's disease is a genetic disease in which a fatty substance (lipid) accumulates in cells and certain organs.
Gaucher's disease is the most common of the lysosomal storage disease
s. It is caused by a hereditary deficiency of the enzyme glucosylceramidase
. The enzyme acts on the fatty acid glucosylceramide. When the enzyme is defective, glucosylceramide accumulates, particularly in white blood cells, most often macrophages (mononuclear leukocytes
). glucosylceramidase can collect in the spleen
, liver, kidney
s, lung
s, brain
and bone marrow.
Symptoms may include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may be painful, severe neurologic
complications, swelling of lymph node
s and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia
, low blood platelet
s and yellow fatty deposits on the white of the eye (sclera
). Persons affected most seriously may also be more susceptible to infection. Some forms of Gaucher's disease may be treated with enzyme replacement therapy.
The disease is caused by a recessive mutation in a gene located on chromosome 1
and affects both males and females. About 1 in 100 people in the United States are carrier
s of the most common type of Gaucher disease, while the carrier rate among Ashkenazi Jews
is 8.9% while the birth incidence is 1 in 450.
The disease is named after
the French doctor Philippe Gaucher
, who originally described it in 1882.
These subtypes have come under some criticism for not taking account of the full spectrum of observable symptoms (the phenotypes.http://www.gaucher.org.uk/consenmarch2002.htm) There are also compound heterozygous variations which considerably increase the complexity of predicting disease course.
lysosomal gluco-cerebrosidase
(also known as beta-glucosidase, ) on the first chromosome
(1q21). The enzyme
is a 55.6 KD, 497 amino acid
s long protein that catalyses the breakdown of glucosylceramide, a cell membrane
constituent of red
and white blood cell
s. The macrophage
s 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 to resemble crumpled-up paper.
In the brain (type II and III), glucosylceramidase accumulates due to the turnover of complex lipid
s during brain development and the formation of the myelin sheath of nerves.
Different mutations in the beta-glucosidase determine the remaining activity of the enzyme, and, to a large extent, the phenotype
.
Heterozygotes for particular acid beta-glucosidase mutations carry about a fivefold risk of developing Parkinson's disease
, making this the most common known genetic risk-factor for Parkinson's. 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.
and genetic testing
is recommended for families who may be carriers of mutations.
Each type has been linked to particular mutations. In all, there are about 80 known mutations, grouped into three main types:
Diaz et al. suggest that the Gaucher-causing mutations entered the Ashkenazi Jewish gene pool in the early Middle Ages (48-55 generations ago).
A diagnosis can also be implied by biochemical abnormalities such as high alkaline phosphatase
, angiotensin-converting enzyme
(ACE) and immunoglobulin levels, or by cell analysis showing "crinkled paper" cytoplasm and glycolipid-laden macrophages.
Some lysosomal enzymes are elevated, including tartrate-resistant acid phosphatase
, hexosaminidase, and a human chitinase, chitotriosidase. This latter enzyme has proved to be very useful for monitoring Gaucher's disease activity in response to treatment, and may reflect the severity of the disease
glucocerebrosidase (imiglucerase
) can dramatically decrease liver
and spleen size, reduce skeletal abnormalities, and reverse other manifestations. This treatment costs approximately $200,000 annually for a single patient and should be continued for life. The rarity of the disease means that dose-finding studies have been difficult to conduct, so there remains controversy over the optimal dose and dosing frequency. Due to the low incidence, this has become an orphan drug
in many countries, meaning that a government recognizes and accommodates the financial constraints that limit research into drugs that address a small population.Velaglucerase alfa
was approved by the Food and Drug Administration
(FDA) as an alternative treatment on February 26, 2010.
Successful bone marrow transplantation cures the non-neurological manifestations of the disease, because it introduces a monocyte
population with active beta-glucosidase. 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. Blood transfusion
may benefit some anemic patients. Other patients may require joint replacement
surgery to improve mobility and quality of life. Other treatment options include antibiotic
s for infections, antiepileptics for seizures, bisphosphonates for bone lesions, and liver transplants. 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.
Gaucher's disease has recently become a target for more than one effort at pharmacological chaperoning
, which involves the use of orally administered drugs that operate at a molecular level. Miglustat
is one of these oral drugs. It was approved for the treatment of this disease in 2003. , another oral drug, isofagomine tartrate
, is under development.
Type 2 Gaucher's disease shows no particular preference for any ethnic group.
Type 3 Gaucher's disease is especially common in the population of the Northern Swedish region of Norrbotten
where the incidence of the disease is 1 in 50,000.
, who originally described it in 1882 and lent his name to the condition. The biochemical basis for the disease would be elucidated in 1965. The first effective treatment for the disease, the drug Ceredase, was approved by the FDA in April 1991. An improved drug, Cerezyme, was approved by the FDA in May 1994 and has replaced the use of Ceredase.
Gaucher's disease is the most common of the lysosomal storage disease
Lysosomal storage disease
Lysosomal storage diseases are a group of approximately 50 rare inherited metabolic disorders that result from defects in lysosomal function...
s. It is caused by a hereditary deficiency of the enzyme glucosylceramidase
Glucosylceramidase
In enzymology, a glucosylceramidase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are D-glucosyl-N-acylsphingosine and H2O, whereas its two products are D-glucose and N-acylsphingosine....
. The enzyme acts on the fatty acid glucosylceramide. When the enzyme is defective, glucosylceramide accumulates, particularly in white blood cells, most often macrophages (mononuclear leukocytes
Mononuclear leukocytes
Mononuclear leukocytes are white blood cells with a one-lobed nucleus. There are two main types of mononuclear leukocytes: monocytes and lymphocytes.Normal hematologic blood values of MLs are about 35% of all white blood cells....
). glucosylceramidase can collect in the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
, liver, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s, lung
Human lung
The human lungs are the organs of respiration in humans. Humans have two lungs, with the left being divided into two lobes and the right into three lobes. Together, the lungs contain approximately of airways and 300 to 500 million alveoli, having a total surface area of about in...
s, brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
and bone marrow.
Symptoms may include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may be painful, severe neurologic
Neurology
Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
complications, swelling of lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, low blood platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s and yellow fatty deposits on the white of the eye (sclera
Sclera
The sclera , also known as the white or white of the eye, is the opaque , fibrous, protective, outer layer of the eye containing collagen and elastic fiber. In the development of the embryo, the sclera is derived from the neural crest...
). Persons affected most seriously may also be more susceptible to infection. Some forms of Gaucher's disease may be treated with enzyme replacement therapy.
The disease is caused by a recessive mutation in a gene located on chromosome 1
Chromosome 1 (human)
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 247 million nucleotide base pairs, which are the basic units of information for DNA...
and affects both males and females. About 1 in 100 people in the United States are carrier
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
s of the most common type of Gaucher disease, while the carrier rate among Ashkenazi Jews
Ashkenazi Jews
Ashkenazi Jews, also known as Ashkenazic Jews or Ashkenazim , are the Jews descended from the medieval Jewish communities along the Rhine in Germany from Alsace in the south to the Rhineland in the north. Ashkenaz is the medieval Hebrew name for this region and thus for Germany...
is 8.9% while the birth incidence is 1 in 450.
The disease is named after
Eponym
An eponym is the name of a person or thing, whether real or fictitious, after which a particular place, tribe, era, discovery, or other item is named or thought to be named...
the French doctor Philippe Gaucher
Philippe Gaucher
Philippe Charles Ernest Gaucher was a French dermatologist born in the department of Nièvre.He received his medical doctorate in 1882, and soon after headed a medical clinic at Necker Hospital. During the subsequent years he was an instructor at several hospital clinics in Paris...
, who originally described it in 1882.
Classification
Gaucher's disease has three common clinical subtypes.- Type I (or non-neuropathic type) is the most common form of the disease, occurring in approximately 1 in 50,000 live births. It occurs most often among persons of Ashkenazi JewishAshkenazi JewsAshkenazi Jews, also known as Ashkenazic Jews or Ashkenazim , are the Jews descended from the medieval Jewish communities along the Rhine in Germany from Alsace in the south to the Rhineland in the north. Ashkenaz is the medieval Hebrew name for this region and thus for Germany...
heritage. Symptoms may begin early in life or in adulthood and include enlarged liverHepatomegalyHepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
and grossly enlarged spleenSplenomegalySplenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
(together hepatosplenomegalyHepatosplenomegalyHepatosplenomegaly is the simultaneous enlargement of both the liver and the spleen . Hepatosplenomegaly can occur as the result of acute viral hepatitis or infectious mononucleosis, or it can be the sign of a serious and life threatening lysosomal storage disease...
); the spleen can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive. Spleen enlargement and bone marrow replacement cause anemia, thrombocytopenia and leukopeniaLeukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
. The brain is not affected pathologically, but there may be lung and, rarely, kidney impairment. Patients in this group usually bruiseBruiseA bruise, also called a contusion, is a type of relatively minor hematoma of tissue in which capillaries and sometimes venules are damaged by trauma, allowing blood to seep into the surrounding interstitial tissues. Bruises can involve capillaries at the level of skin, subcutaneous tissue, muscle,...
easily (due to low levels of platelets) and experience fatigue due to low numbers of red blood cells. Depending on disease onset and severity, type 1 patients may live well into adulthood. Many patients have a mild form of the disease or may not show any symptoms.
- Type II (or acute infantile neuropathic Gaucher's disease) typically begins within 6 months of birth and has an incidence rate of approximately 1 in 100,000 live births. Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, spasticitySpasticitySpasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
, seizureSeizureAn epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age 2.
- Type III (the chronic neuropathic form) can begin at any time in childhood or even in adulthood, and occurs in approximately 1 in 100,000 live births. It is characterized by slowly progressive but milder neurologic symptoms compared to the acute or type 2 version. Major symptoms include an enlarged spleen and/or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia and respiratory problems. Patients often live into their early teen years and adulthood.
These subtypes have come under some criticism for not taking account of the full spectrum of observable symptoms (the phenotypes.http://www.gaucher.org.uk/consenmarch2002.htm) There are also compound heterozygous variations which considerably increase the complexity of predicting disease course.
Signs and symptoms
- Painless hepatomegalyHepatomegalyHepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
and splenomegalySplenomegalySplenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
: the size of the spleen can be 1500-3000 ml, as opposed to the normal size of 50-200 ml. Splenomegaly may decrease the affected individual's capacity for eating by exerting pressure on the stomach. While painless, enlargement of spleen increases the risk of splenic rupture. - Hypersplenism and pancytopeniaPancytopeniaPancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
: the rapid and premature destruction of blood cells, leading to anemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, neutropeniaNeutropeniaNeutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
, leukopeniaLeukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
, and thrombocytopeniaThrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
(with an increased risk of infectionInfectionAn infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
and bleedingBleedingBleeding, technically known as hemorrhaging or haemorrhaging is the loss of blood or blood escape from the circulatory system...
). - CirrhosisCirrhosisCirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
of the liver is rare - Severe pain associated with joints and bones, frequently presenting in hips and knees.
- NeurologicalNeurologyNeurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
symptoms occur only in some types of Gaucher's (see below):- Type II: serious convulsions, hypertonia, mental retardation, apnea.
- Type III: muscle twitches known as myoclonusMyoclonusMyoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...
, convulsions, dementia, ocular muscle apraxia.
- OsteoporosisOsteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
: 75% develop visible bony abnormalities due to the accumulated glucosylceramide. A deformity of the distal femurFemurThe femur , or thigh bone, is the most proximal bone of the leg in tetrapod vertebrates capable of walking or jumping, such as most land mammals, birds, many reptiles such as lizards, and amphibians such as frogs. In vertebrates with four legs such as dogs and horses, the femur is found only in...
in the shape of an Erlenmeyer flaskErlenmeyer flaskAn Erlenmeyer flask, also known as a conical flask, is a widely used type of laboratory flask which features a flat bottom, a conical body, and a cylindrical neck. It is named after the German chemist Emil Erlenmeyer, who created it in 1861...
is commonly described (aseptic necrosis of the femur joint). - Yellowish-brown skin pigmentation
Pathophysiology
The disease is caused by a defect in housekeeping geneHousekeeping gene
A housekeeping gene is typically a constitutive gene that is required for the maintenance of basic cellular function, and are found in all cells of an organism. Although some housekeeping genes are expressed at relatively constant levels , other housekeeping genes may vary depending on...
lysosomal gluco-cerebrosidase
Glucocerebrosidase
β-Glucocerebrosidase is an enzyme with glucosylceramidase activity that is needed to cleave, by hydrolysis, the beta-glucosidic linkage of the chemical glucocerebroside, an intermediate in glycolipid metabolism...
(also known as beta-glucosidase, ) on the first chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
(1q21). The enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
is a 55.6 KD, 497 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s long protein that catalyses the breakdown of glucosylceramide, a cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
constituent of red
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
and white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s. The macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s 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 to resemble crumpled-up paper.
In the brain (type II and III), glucosylceramidase accumulates due to the turnover of complex lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
s during brain development and the formation of the myelin sheath of nerves.
Different mutations in the beta-glucosidase determine the remaining activity of the enzyme, and, to a large extent, the phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
.
Heterozygotes for particular acid beta-glucosidase mutations carry about a fivefold risk of developing Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, making this the most common known genetic risk-factor for Parkinson's. A study of 1525 Gaucher patients in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
suggested that while cancer risk is not elevated, particular malignancies (non-Hodgkin lymphoma
Non-Hodgkin lymphoma
The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
, melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
and pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
) occurred at a 2-3 times higher rate.
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 counselingGenetic counseling
Genetic counseling or traveling 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 or transmitting it, and the options open to them in management and family planning...
and genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
is recommended for families who may be carriers of mutations.
Each type has been linked to particular mutations. In all, there are about 80 known mutations, grouped into three main types:
- Type I (N370S homozygote), the most common, also called the "non-neuropathic" type occurs mainly in Ashkenazi Jews, at 100 times the occurrence in the general populace. The median age at diagnosis is 28 years of age, and life expectancy is mildly decreased. There are no neurological symptoms.
- Type II (1 or 2 alleleAlleleAn allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s L444P) is characterized by neurological problems in small children. The enzyme is hardly released into the lysosomeLysosomethumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
s. Prognosis is dismal: most die before reaching the third birthday. - Type III (also 1-2 copies of L444P, possibly delayed by protective polymorphisms) occurs in SwedishSwedenSweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....
patients from the NorrbottenNorrbottenNorrbotten is a Swedish province in northernmost Sweden. It borders south to Västerbotten, west to Swedish Lapland, and east to Finland.- Administration :...
region. This group develops the disease somewhat later, but most die before their 30th birthday.
Diaz et al. suggest that the Gaucher-causing mutations entered the Ashkenazi Jewish gene pool in the early Middle Ages (48-55 generations ago).
Diagnosis
A definitive diagnosis is made with genetic testing. As there are numerous different mutations, sequencing of the beta-glucosidase gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available, and is useful when there is a known genetic risk factor.A diagnosis can also be implied by biochemical abnormalities such as high alkaline phosphatase
Alkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
, angiotensin-converting enzyme
Angiotensin-converting enzyme
Angiotensin I-converting enzyme , an exopeptidase, is a circulating enzyme that participates in the body's renin-angiotensin system , which mediates extracellular volume , and arterial vasoconstriction...
(ACE) and immunoglobulin levels, or by cell analysis showing "crinkled paper" cytoplasm and glycolipid-laden macrophages.
Some lysosomal enzymes are elevated, including tartrate-resistant acid phosphatase
Acid phosphatase
Acid phosphatase is a phosphatase, a type of enzyme, used to free attached phosphate groups from other molecules during digestion. It is basically a phosphomonoesterase...
, hexosaminidase, and a human chitinase, chitotriosidase. This latter enzyme has proved to be very useful for monitoring Gaucher's disease activity in response to treatment, and may reflect the severity of the disease
Treatment
For type 1 and most type 3 patients, enzyme replacement treatment with intravenous recombinantRecombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
glucocerebrosidase (imiglucerase
Imiglucerase
Imiglucerase is a medication used in the treatment of Gaucher's disease.It is a recombinant DNA-produced analogue of human β-glucocerebrosidase....
) can dramatically decrease liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and spleen size, reduce skeletal abnormalities, and reverse other manifestations. This treatment costs approximately $200,000 annually for a single patient and should be continued for life. The rarity of the disease means that dose-finding studies have been difficult to conduct, so there remains controversy over the optimal dose and dosing frequency. Due to the low incidence, this has become an orphan drug
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
in many countries, meaning that a government recognizes and accommodates the financial constraints that limit research into drugs that address a small population.Velaglucerase alfa
Velaglucerase alfa
Velaglucerase alfa , manufactured by Shire plc is a hydrolytic lysosomal glucocerebroside-specific enzyme, which is a recombinant form of glucocerebrosidase indicated as a long-term enzyme replacement therapy for those suffering of Gaucher disease Type 1. It has an identical amino acid sequence to...
was approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) as an alternative treatment on February 26, 2010.
Successful bone marrow transplantation cures the non-neurological manifestations of the disease, because it introduces a monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
population with active beta-glucosidase. However, this procedure carries significant risk and is rarely performed in Gaucher patients. Surgery to remove the spleen (splenectomy
Splenectomy
A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...
) may be required on rare occasions if the patient is anemic or when the enlarged organ affects the patient’s comfort. Blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
may benefit some anemic patients. Other patients may require joint replacement
Replacement joint
Replacement arthroplasty [from Greek arthron, joint, limb, articulate, + -plassein, to form, mould, forge, feign, make an image of], or joint replacement surgery, is a procedure of orthopedic surgery in which the arthritic or dysfunctional joint surface is replaced with an orthopaedic prosthesis...
surgery to improve mobility and quality of life. Other treatment options include antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s for infections, antiepileptics for seizures, bisphosphonates for bone lesions, and liver transplants. 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
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
may be a future step.
Gaucher's disease has recently become a target for more than one effort at pharmacological chaperoning
Pharmacological chaperone
A pharmacological chaperone is a small molecule that enters cells and serves as a molecular scaffolding in order to cause otherwise-misfolded mutant proteins to fold and route correctly within the cell....
, which involves the use of orally administered drugs that operate at a molecular level. Miglustat
Miglustat
Miglustat is a drug developed by and is used primarily to treat Type 1 Gaucher disease . It is marketed under the trade name Zavesca. Miglustat is an imino sugar , a synthetic analogue of D-glucose and a white to off-white crystalline solid that has a bitter taste...
is one of these oral drugs. It was approved for the treatment of this disease in 2003. , another oral drug, isofagomine tartrate
Isofagomine tartrate
Isofagomine tartrate is an experimental drug for the treatment of certain forms of Gaucher's disease, developed by Amicus Therapeutics and Shire plc....
, is under development.
Epidemiology
The National Gaucher Foundation states that around 1 in 100 people in the general U.S. population is a carrier for type 1 Gaucher's disease, giving a prevalence of 1 in 40,000: among Ashkenazi Jews the rate of carriers is considerably higher, at roughly 1 in 15.Type 2 Gaucher's disease shows no particular preference for any ethnic group.
Type 3 Gaucher's disease is especially common in the population of the Northern Swedish region of Norrbotten
Norrbotten
Norrbotten is a Swedish province in northernmost Sweden. It borders south to Västerbotten, west to Swedish Lapland, and east to Finland.- Administration :...
where the incidence of the disease is 1 in 50,000.
History
The disease was first recognised by the French doctor Philippe GaucherPhilippe Gaucher
Philippe Charles Ernest Gaucher was a French dermatologist born in the department of Nièvre.He received his medical doctorate in 1882, and soon after headed a medical clinic at Necker Hospital. During the subsequent years he was an instructor at several hospital clinics in Paris...
, who originally described it in 1882 and lent his name to the condition. The biochemical basis for the disease would be elucidated in 1965. The first effective treatment for the disease, the drug Ceredase, was approved by the FDA in April 1991. An improved drug, Cerezyme, was approved by the FDA in May 1994 and has replaced the use of Ceredase.
See also
- Niemann-Pick diseaseNiemann-Pick diseaseNiemann–Pick disease refers to a group of fatal inherited metabolic disorders that are included in the larger family of lysosomal storage diseases .-Signs and symptoms:Symptoms are related to the organs in which they accumulate...
- Fabry disease
- Tay-Sachs
- Krabbe diseaseKrabbe diseaseKrabbe disease is a rare, often fatal degenerative disorder that affects the myelin sheath of the nervous system. This condition is inherited in an autosomal recessive pattern...
- Metachromatic leukodystrophyMetachromatic leukodystrophyMetachromatic leukodystrophy is a lysosomal storage disease which is commonly listed in the family of leukodystrophies. Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous...
- Medical genetics of Ashkenazi Jews