Niemann-Pick Disease: Symptoms and General Information
Author: Thomas C. Weiss : Contact: Disabled World
Published: 2010-03-10 : (Rev. 2019-04-02)
Synopsis and Key Points:
Niemann-Pick Disease is one of a group of lysosome storage disease that affect the metabolism caused by mutations in the genes.
There are three commonly recognized forms of Niemann-Pick Disease; types A, B and C.
Nieman-Pick types A and B (NPA and NPB)
Also referred to as, 'Acid Sphingomyelinase Deficiency (ASMD), and are caused by the deficiency of the enzyme acid sphingomyelinase (ASM) which is found in special compartments within a person's cells called, 'lysosomes.' Acid Sphingomyelinase is something that is required in order to metabolize a lipid called, 'sphingomelin.' If ASM is either functioning inappropriately or absent entirely in a person's system, sphingomyelin is unable to be metabolized properly and accumulates within a person's cells, eventually causing cell death and malfunction of the person's major organ systems.
Both NPA and NPB are caused by the same enzymatic deficiency. There is growing evidence that these two forms of Nieman-Pick disease are representative of both ends of a continuum. People who are affected by NPA commonly have little to no ASM production, usually less than one-percent. People with NPB have around ten-percent of the average level of ASM, on the other hand. The clinical prognosis for people with NPA and NPB is quite different. People with NPA experience a severe neurologic disease that leads to death by the age of between two and four years.
People with NPB, on the other hand, commonly experience little to no neurologic involvement and might live into late childhood or even adulthood. People with NPB commonly have respiratory problems, as well as enlargement of the liver and spleen, which can lead to cardiovascular stress and heart disease later in life. Approximately one-thousand two-hundred people have Niemann-Pick disease around the world today, with most of these people experiencing NPB, or an intermediate form of the disease.
Niemann-Pick Disease - Type C
Niemann-Pick Type C (NPC) is markedly different from the other types of the disease. People with NPC are unable to metabolize cholesterol and additional forms of lipids appropriately within their cells. As a consequence, cholesterol accumulates within their spleen and liver, and lipids accumulate in their brain. NPC also causes a secondary reduction of ASM activity in people with this form of the disease, which has led to all three types of the disease being considered forms of the same disease.
There is a notable variation in the timing of when people with NPC first experience symptoms, as well as the progression of the disease. The symptoms of NPC can begin to appear as early as the first few months of life, or as late as adulthood. The person may experience, 'vertical gaze palsy,' or the inability to move their eyes up and down. They may also experience enlargement of their spleen or liver, as well as jaundice as a child. The symptoms mentioned are strong indications that NPC is a consideration. It should be noted that it is common for only one or two of these symptoms to appear during the early stages of the disease. In the majority of people with NPC, neurological symptoms begin to appear between the ages of four and ten years. The later the neurological symptoms begin, the slower the disease commonly progresses.
There are approximately five-hundred people who have been diagnosed with NPC in the world today. The number of people with the disease is believed to be higher, but the difficulties associated with diagnosis do not permit an accurate assessment of the rate of occurrence. NPC has been initially diagnosed as a form of learning disability, mild retardation, 'clumsiness,' and delayed development of fine motor skills. Families commonly spend a number of years seeking a diagnosis of NPC before it is identified. NPC is always fatal, with the vast majority of those affected by the disease dying prior to age twenty; the majority die before the age of ten. A late onset may lead to a longer lifespan, although it is exceedingly rare for a person with NPC to reach the age of forty.
Niemann-Pick Disease affects every segment of the population, with people in North and South America, Africa, Europe, Asia, and Australia experiencing the disease. There is; however, a higher incidence rate among certain populations:
- Ashkenazi Jewish population (NPA and NPB)
- Maghreb region (Tunisia, Morocco, and Algeria) of North Africa (NPB)
- Spanish-American population of southern New Mexico and Colorado (NPC)
- French Canadian population of Nova Scotia (type D - now considered a variant of NPC)
Diagnosing Niemann-Pick Disease
Every type of Nieman-Pick Disease is, 'autosomal recessive,' meaning that children with the disease have two copies of the gene responsible for it. Each parent has one copy of the gene and does not present any signs of the disease. Siblings of the parents can also carry the gene. When both of a child's parents have the gene for Niemann-Pick disease, there is a twenty-five percent chance their child with have the disease. There is a fifty-percent chance their child will carry the gene, and a twenty-five percent chance that their child will not have the disease, and not carry the gene. Carrier detection for all families is not yet considered to be reliable.
The mutations for both NPA and NPB have been studied extensively, in particular among the Ashkenazi Jewish population. DNA tests for these forms of Nieman-Pick disease are available. Antenatal diagnosis of the disease is available through a limited number of centers in the world. Dr. Wenda Greer of Dalhousie University has identified the genetic mutation related to Type D of the disease, which is now referred to as the, 'Nova Scotia,' variant of NPC. Carrier detection is possible for other families only once their particular mutation has been identified.
It is important to know the symptoms of Niemann-Pick disease, and be able to recognize them. If your child experiences any of the following symptoms it may indicate Niemann-Pick disease. While the disease is rare, it may not be as rare is it is thought to be due to the difficulty of diagnosing it. The symptoms of the disease can include:
- Slurred Speech
- Learning Problems
- Jaundice Following Birth
- Abdominal Enlargement
- Hypersensitivity to Touch
- Repeated Lung Infections
- Unusual Shortness of Breath
- Sudden Loss of Muscle Tone
- Cherry Red Spot Inside the Eye
- Vertical Eye Movement Difficulties
- Feeding and Swallowing Difficulties
- Enlargement of the Spleen or Liver
- Progressive Loss of Early Motor Skills
NPA and NPB are by measuring the level of activity of the enzyme acid Sphingomyelinase (ASM) in a person's white blood cells. A blood sample is drawn from people who are believed to have the disease, and testing is available at a number of commercial laboratories in America and elsewhere. While the testing is able to identify people with NPA and NPB, it is not very reliable for the detection of people who have only one functional copy of the ASM gene referred to as, 'carriers.' In addition, the test will show decreased ASM activity, yet is unable to always predict whether or not the person being tested will have NPA or NPB, or an intermediate variant of the disease. Determining a variant of the disease requires clinical evaluation of the particular individual.
The Mount Sinai Department of Human Genetics has identified certain populations where specific mutations account for a high percentage of people with ASM deficiency. In relation to NPA, certain mutations account for greater than ninety-five percent of genetic changes that cause disease in the Ashkenazi Jewish population. Direct testing of people in this particular population for these three changes is used for carrier identification. In other populations, the mutations have to be identified first in people who are affected before DNA carrier testing can be performed for family members. Recently, comprehensive analysis of the entire ASM gene structure has been used for carrier testing for partners of known NPA carriers, something that is available at a number of laboratories in America.
Molecular genetic testing is available at this time on a commercial basis for NPB at a number of laboratories. Health care providers should contact laboratory personnel to arrange for such testing for interested people. Once a person who has been affected by Niemann-Pick disease has been tested and the particular mutation affecting has been identified, it becomes possible to diagnose NPB carriers through DNA testing within the person's family.
Niemann-Pick Type C (NPC) is a very rare and variable condition; one that might not be recognized by some health care providers. Specialists who do suspect NPC in a person can make a diagnosis by taking a skin biopsy, growing cells in the laboratory, and studying the cells ability to transport and store cholesterol. The transport of cholesterol in cells is studies by measuring conversion of the cholesterol from one form to another, referred to as, 'esterification.' Storage of cholesterol can be assessed by staining the cells with a chemical that glows underneath an ultraviolet light source. Doing so can demonstrate whether or not the cholesterol is being appropriately stored in lysosomes. Performance of both the transport and storage test is important because reliance on either one or the other may lead to a misdiagnosis, or a missed diagnosis of a variant form of NPC.
Should a health care professional suspect NPC in a person there are only two laboratories in America that perform diagnostic testing in relation to it. One of these laboratories is the Mayo Clinic Biochemical Genetics Laboratory in Rochester, MN. The other is the Lysosomal Disease Testing Laboratory at Thomas Jefferson University in Philadelphia, PA. Laboratory personnel are not permitted to discuss testing with either patients or their family members directly, so it is important that the person's health care provider contact the laboratory. The health care provider will be given directions for collecting the sample, as well as sending it to the laboratory for proper analysis.
The year 1997 found the NPC1 gene being identified. Mutations in the gene are responsible for around ninety-five percent of all people with NPC. Since that time, greater than two-hundred and fifty mutations related to NPC have been identified in this particular gene, as well as in the second NPC gene, referred to as, 'NPC2.' In all, approximately ninety-five percent of those affected, it is possible to identify the genetic changes that have caused the disease if the diagnosis of NPC has been confirmed through testing first. The fact that there are so many unique mutations in these genes; however, as well as people with classic NPC in whom mutations have not been identified, means that it is not optimal to use genetic testing as a general diagnostic tool. Genetic testing may be done to identify family members who are carriers where the mutations is known. Genetic testing has also been used to assist in better identifying the carrier risk for partners of known carriers.
There are three laboratories in the United States that perform genetic testing for NPC. One is in Gaithersburg, MD. Another laboratory is the Mayo Clinic Genetic Laboratory. The third laboratory that performs genetic testing in relation to NPC is Emory Molecular Genetics Laboratory. The person with NPC's family should have their health care provider contact the appropriate laboratory.
Treating Niemann-Pick Disease
Medical science has not discovered a form of treatment for NPA at this time. Supportive forms of treatment can assist in management of the symptoms of NPA. People with NPA might require assistance from:
- A Pulmonologist for respiratory problems
- A Cardiologist for heart problems
- Liver and spleen specialists
- A Gastroenterologist
- Physical therapists
Since the early 1990's, research into therapies for NPB have progressed at a rapid rate. The Mount Sinai School of Medicine is conducting research related to bone marrow transplantation, gene therapy, and enzyme replacement therapy. These forms of therapy have proven effective against NPB in laboratory conditions. Bone marrow transplantation has proven effective in mouse models for various aspects of NPB when the transplant takes place early in life. Due to the complexity of the bone transplantation medical procedure, it has only been conducted a few times on human beings who experience NPB. The results of the transplants have been mixed.
Enzyme replacement therapy has been tested on mice as well, and has been shown to be effective for NPB. The form of therapy has also been successful in other lysosomal storage disease, to include Fabry's and Gaucher Type I. Both Mount Sinai Medical Center and Genzyme Corporation have started clinical trials of enzyme replacement therapy for older persons with NPB.
Gene therapy would permit the defective gene to be replaced by healthy genes. Constructive results of this form of therapy have been obtained with individual cells. However, testing in relation to Niemann-Pick disease and mice is only beginning.
Supportive forms of treatment may assist in the management of symptoms related to NPB as well. Support that people affected by NPB may require can be received from:
- A Pulmonologist for respiratory problems
- A Cardiologist for heart problems
- Liver and spleen specialists
- A Gastroenterologist
- Learning specialists
- Physical therapists
Physicians may now prescribe a medication, 'Zavesca,' for treatment of NPC; however, the medication still needs to be cleared by the U.S. FDA before it can be marketed specifically for that use. Patient advocates say that insurers are hesitant to pay for the medication for people with NPC without U.S. FDA approval. The FDA commonly follows panel recommendations when deciding whether or not to approve medications. A decision regarding Zavesca is due by March tenth.
There is an advisory committee that is made up of both clinical and medical experts who will recommend to the FDA that Zavesca be approved for use in relation to Niemann-Pick disease Type C. The committee reviewed data related to the medication, and has heard testimony and statements from doctors, scientists, and families affected by NPC in a review on January 12th. Should the FDA approve the use of Zavesca for the treatment of NPC it will be a historic step because it would be the first authorized treatment for the symptoms of the disease in America.
UPDATE: NO Approval of Miglustat (Zavesca) for USA
Miglustat, marketed under the trade name Zavesca, is the first treatment to be approved for treating progressive neurological complications in people with Niemann–Pick disease, type C (NPC) has been approved in Europe in 2009, Canada in 2010, and Japan in 2012, but the U.S. FDA DECLINED to approve it in 2010 and called for more data...
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