Ailmemts & Remedies

Gaucher’s disease

Alternative Names:  Glucocerebrosidase deficiency; Glucosylceramidase deficiency

Gaucher’s disease is a very rare 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 diseases:536 It is caused by a hereditary deficiency of the enzyme glucocerebrosidase . The enzyme acts on a fatty substance glucocerebroside (also known as glucosylceramide). When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells (mononuclear leukocytes). Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain and bone marrow….CLICK & SEE THE PICTURES

Symptoms may include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may be painful, 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 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 carriers 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 and lent his name to the condition.The biochemical basis for the disease would be elucidated in 1965.

Gaucher’s disease can occur at any age. It’s most common in Eastern and Central European (Ashkenazi) Jewish people.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 where the incidence of the disease is 1 in 50,000.

Signs and symptoms of Gaucher’s disease can vary widely from one person to another, particularly among different types of the disease.

The major types of Gaucher’s disease and associated symptoms are:

Type 1. This form of the disease is the most common and is generally the most mild. Type 1 accounts for about 90 percent of cases. In this form of the disease, there’s usually no damage to the brain. This type can occur at any age, although it’s most prevalent in adults, with an average age of 30 at the time of diagnosis. Possible signs and symptoms of type 1 Gaucher’s disease include:
*Skeletal abnormalities, including thinning of your bones (osteopenia), bone pain and bone fractures
*Enlarged liver (hepatomegaly) or spleen (splenomegaly), or both
*A decrease in healthy red blood cells (anemia)
*Excessive fatigue
*A greater susceptibility to bruising, which may mean you have a low number of blood platelets (thrombocytopenia)
*Yellow spots in your eyes (pingueculae)
*Delayed puberty

Type 2. This form of Gaucher’s disease is rare and much more severe than the other types. It begins during the first year of life, often developing by 3 months. These babies have brain damage that is extensive and progresses rapidly. In addition to the signs and symptoms listed above, other possible problems that may occur with this type of Gaucher’s include:
*Cognitive deterioration, including mental retardation or dementia

Type 3. This form of Gaucher’s disease, also rare, usually begins in childhood or adolescence. It tends to be chronic and progresses more slowly than does type 2.
Although the brain is affected, brain involvement tends to be milder than in type 2. Signs and symptoms, such as enlargement of the liver and spleen, tend to vary more in intensity than in type 2. Signs and symptoms that may occur more in type 3 than in type 1 include:

*Cognitive deterioration, including mental retardation or dementia
*Abnormal eye movements
*Loss of muscle coordination

The disease is caused by a defect in the housekeeping gene lysosomal gluco-cerebrosidase (also known as beta-glucosidase, EC, PDB 1OGS) on the first chromosome (1q21). The enzyme is a 55.6 KD, 497 amino acids long protein that catalyses the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. 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 to resemble crumpled-up paper.

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.

Different mutations in the beta-glucosidase determine the remaining activity of the enzyme, and, to a large extent, the phenotype.

Risk Factors:
The risk of having type 1 or 3 Gaucher’s disease or being a carrier is higher if you’re of Eastern or Central European (Ashkenazi) Jewish ancestry. Type 2 is more common in people of Swedish descent.

A family history of any type of Gaucher’s disease increases the risk of being either a carrier of Gaucher’s or of developing the disease.

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

Complications of all types
Possible complications of all types of Gaucher’s disease include:

*Bone pain, which can become severe and incapacitating and may be associated with fractures.

*A tendency to bleed, which may result in repeated hemorrhaging in the nostrils or nasal cavities, or bruising beneath the skin (ecchymosis).

*An increased risk of certain cancers. Older people with Gaucher’s disease may have an increased likelihood of developing certain types of cancer, particularly multiple myeloma — uncontrolled multiplication of plasma cells.

Complications of type 2
Complications that are more likely to occur in people with type 2 Gaucher’s disease often include serious neurological complications, such as:

*Abnormal gait
*Swallowing problems

As these problems progress and become more severe, they can become debilitating and lead to death.

Complications of type 3
People with type 3 Gaucher’s disease are more likely to develop calcification of heart valves, which damages the valves and makes it increasingly difficult for them to open fully and function properly.

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, 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

For type 1 and most type 3 patients, enzyme replacement treatment with intravenous recombinant 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 antibiotics 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.

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 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. As of June 2009[update], another oral drug, isofagomine tartrate, is under development.

How well a person does depends on the subtype of the disease. The infantile form of Gaucher disease may lead to early death. Most affected children die before age 5.

Adults with the type 1 form of the disease can expect normal life expectancy with enzyme replacement therapy.

Genetic counseling is recommended for prospective parents with a family history of Gaucher disease. Testing can determine if parents carry the gene that could pass on the Gaucher disease. A prenatal test can also tell if the fetus has Gaucher syndrome.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.


Ailmemts & Remedies

Fabry disease

Alternative Name: Fabry’s disease, Anderson-Fabry disease, angiokeratoma corporis diffusum and alpha-galactosidase A deficiency

Fabry disease results from abnormal deposits of a particular fatty substance (called globotriaosylcera-mide) in blood vessel walls throughout the body. The primary defect which allows this to occur is the inherited deficiency of the enzyme, alpha galactosidase A, which is normally responsible for the breakdown of globotriaosylceramide

Metabolic Defect:
The body continuously performs metabolic processes which produce, recycle and remove vital compounds. In patients with Fabry disease one such common compound formed of three sugars and a fatty substance (globotriaosylceramide) does not get broken down due to the missing or non-functioning enzyme alpha galactosidase A. Since this fatty compound (lipid) is not being broken down and removed, it begins to accumulate. Thus, Fabry disease is often referred to as a “storage disorder” due to this abnormal accumulation. In patients with Fabry disease, this accumulation occurs primarily in the blood and in the walls of blood vessels. As the abnormal storage of this fatty compound increases with time, the channels of these vessels become narrowed, leading to decreased blood flow and decreased nourishment of the tissues normally supplied by these vessels. This abnormal process occurs in blood vessels throughout the body, particularly affecting vessels in the skin, kidneys, heart, brain and nervous system.


Disease Inheritance:
Fabry disease is an inherited disorder. The defective gene is on the X-chromosome, which is one of the two chromosomes that determine an individual’s sex. Females have two X chromosomes, one inherited from each of their parents. Males have one X chromosome inherited from their mother and one Y chromosome inherited from their father. A female with Fabry receive one X chromosome with a defective gene and one X chromosome with the normal gene, and thus often has some protection from the major manifestations of the disease. This is not always the case though as there is a high degree of variability in females. Males with Fabry disease receive only one abnormal X chromosome that contains the abnormal gene and thus express the disease.


All male and female children of an affected female have a 50% chance of inheriting the defective gene from their mother. If the father is the one carrying the Fabry gene all female children will inherit the defective gene and all male children will not. The inheritance pattern of Fabry disease is called X-linked inheritance. Fabry disease occurs in all ethnic groups. It is estimated that one person in 40,000 has Fabry disease.

Symptoms are typically first experienced in early childhood and can be very difficult to understand; the rarity of Fabry disease to many clinicians sometimes leads to misdiagnoses. Manifestations of the disease usually increase in number and severity as an individual ages.

Full body or localized pain to the extremities (known as acroparesthesia) or GI tract is common in patients with Fabry disease. Acroparesthesia in Fabry disease is believed to be related to the damage of peripheral nerve fibers that transmit pain. GI tract pain is likely caused by accumulation of lipids in the small vasculature of the GI tract which obstructs blood flow and causes pain.

Renal involvement
Kidney complications are a common and serious effect of the disease; renal insufficiency and renal failure may worsen throughout life. Proteinuria (which causes foamy urine) is often the first sign of kidney involvement. End stage renal failure in males can typically occur in the third decade of life, and is a common cause of death due to the disease.

You may click to see different pictures of  Fabry disease

Cardiac manifestations
Cardiac complications occur when glycolipids build up in different heart cells; heart related effects worsen with age and may lead to increased risk of heart disease. Hypertension (high blood pressure) and cardiomyopathy are commonly observed.

Dermatological manifestations
Angiokeratomas (tiny, painless papules that can appear on any region of the body, but are predominant on the thighs, around the belly-button, buttocks, lower abdomen, and groin) are a common symptom.

Anhidrosis (lack of sweating) is a common symptom, and less commonly hyperhidrosis (excessive sweating).

Additionally, patients can exhibit Raynaud’s disease-like symptoms with neuropathy (in particular, burning extremity pain).

Ocular manifestations
Cosmetic ocular involvement may be present showing cornea verticillata (also known as vortex keratopathy), i.e. clouding of the corneas. Keratopathy may be the presenting feature in asymptomatic carriers, and must be differentiated from other causes of vortex keratopathy (e.g. drug deposition in the cornea). This clouding does not affect vision.


Other ocular findings that can be seen include conjunctival aneurysms, posterior spoke-like cataracts, papilloedema, macular edema, optic atrophy and retinal vascular dilation.

Other manifestations;
Fatigue, neuropathy (in particular, burning extremity pain), cerebrovascular effects leading to an increased risk of stroke, tinnitus (ringing in the ears), vertigo, nausea, inability to gain weight, chemical inbalances, and diarrhea are other common symptoms.

Fabry disease is a type of lipid storage disease caused by a defect in the gene that controls an enzyme called alpha-galactosidase A (also known as ceramide trihexosidase). This enzyme is involved in the breakdown of certain lipids (fats).

The deficiency in this enzyme causes certain lipid molecules, called glycosphingolipids, to accumulate in the body’s tissues, particularly the heart, kidneys, eyes and nerve tissue.

The gene that’s altered is on the X chromosome, making its transmission X-linked. So boys have a 50 per cent chance of inheriting the disorder, while girls have a 50 per cent chance of becoming a carrier. The gene responsible can be detected.

Fabry disease is indicated when associated symptoms are present, and can be diagnosed by a blood test to measure the level of alpha-galactosidase activity, however this may be misleading in female carriers due to the random nature of X-inactivation. Chromosomal analysis of the GLA gene is the most accurate method of diagnosis, and many mutations which cause the disease have been noted. Kidney biopsy may also be suggestive of Fabry Disease if excessive lipid buildup is noted.

You may click to see :Final Diagnosis — Fabry’s Disease

Naturally, alpha-galactosidase A (a-GAL A) is likely to be present only at very low levels in the blood, particularly in males. In females, owing to X-inactivation patterns, levels are commonly normal even if the patient is not asymptomatic. The Sifap (stroke in young Fabry patients) project will investigate the relation between stroke and Fabry’s disease.

Misdiagnosis of Fabry Disease:  Pediatricians as well as internists commonly misdiagnose Fabry disease

There’s no cure for Fabry disease, although it may be treated by enzyme replacement.

Until the 2000s, treatment of Fabry disease targeted the symptomatic effects.

In 2001, three Enzyme Replacement Therapies (ERTs) were released: Agalsidase alpha (Replagal, manufactured by Shire) and Agalsidase beta (Fabrazyme, manufactured by Genzyme). These attempt to replace the deficient enzyme by means of infusion, most commonly, every two weeks. The cost of these drugs is problematic (approximately $250,000 US a year/patient) and remains a barrier to many patients in some countries. The infusion may be performed by the patient themselves, in the patient’s home by a registered nurse, or at a medical facility. Enzyme replacement therapy is not a cure, but can allow normal metabolism and both prevent disease progression as well as potentially reverse symptoms.

Pain in Fabry disease responds to ERT, but pain management regimens may also include analgesics, anticonvulsants, and non-steroidal anti-inflammatory drugs.

Patients with Fabry disease often survive into adulthood but are at increase risk of strokes, heart attack and heart disease, and kidney failure.

The National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health, conducts and supports research to find ways to treat and prevent lipid storage diseases such as Fabry disease. This research includes clinical studies by the NINDS Developmental and Metabolic Neurology Branch:

For more information:

Fabry Support & Information Group
108 NE 2nd Street, Ste. C
P.O. Box 510 Concordia, MO 64020-0510
Tel: 660-463-1355
Fax: 660-463-1356

National Tay-Sachs and Allied Diseases Association
2001 Beacon Street Suite 204
Brighton, MA 02135
Tel: 617-277-4463 800-90-NTSAD (906-8723)
Fax: 617-277-0134

National Organization for Rare Disorders (NORD)
P.O. Box 1968 (55 Kenosia Avenue)
Danbury, CT 06813-1968


Tel: 203-744-0100
Voice Mail 800-999-NORD (6673)
Fax: 203-798-2291

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.


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