Niemann-Pick Disease: Symptoms and General Information
Synopsis: Niemann-Pick Disease is one of a group of lysosome storage diseases that affect the metabolism caused by mutations in the genes. Niemann-Pick Disease affects every population segment, with people in North and South America, Africa, Europe, Asia, and Australia experiencing the disease. There is, however, a higher incidence rate among specific populations. 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 condition. 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 has yet to be considered to be reliable.
There are three commonly recognized forms of Niemann-Pick Disease; types A, B, and C.
The U.S. Social Security Administration (SSA) has included Niemann-Pick Disease (NPD) - Type A and Niemann-Pick Type C as Compassionate Allowances to expedite a disability claim.
Nieman-Pick types A and B (NPA and NPB)
Also referred to as, 'Acid Sphingomyelinase Deficiency (ASMD), and is 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 required to metabolize a lipid called, 'sphingomyelin.' If ASM is either malfunctioning or absent entirely in a person's system. In that case, sphingomyelin cannot be metabolized properly and accumulates within a person's cells, eventually causing cell death and malfunctioning the person's major organ systems.
Both the same enzymatic deficiency causes NPA and NPB. There is growing evidence that these two forms of Nieman-Pick disease are representative of both ends of a continuum. People affected by NPA commonly have little to no ASM production, usually less than one percent. On the other hand, people with NPB have around ten percent of the average level of ASM. 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 and 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 cannot appropriately metabolize cholesterol and other lipids within their cells. Consequently, 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 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 and the progression of the disease. The symptoms of NPC can 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. As a child, they may also experience enlargement of their spleen or liver and jaundice. 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 most people with NPC, neurological symptoms appear between the ages of four and ten years. The later the neurological symptoms begin, the slower the disease commonly progresses.
Approximately five-hundred people have been diagnosed with NPC today. The number of people with the disease is believed to be higher, but the difficulties associated with the 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 several 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 before age twenty; the majority die before age 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 population segment, 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 worldwide. 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 recognize them. If your child experiences the following symptoms, it may indicate Niemann-Pick disease. While the disease is rare, it may not be as rare as it is thought to be due to its difficulty. 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 measured by the activity level of the enzyme acid Sphingomyelinase (ASM) in a person's white blood cells. A blood sample is drawn from people believed to have the disease, and testing is available at several commercial laboratories in America and elsewhere. While the testing can identify people with NPA and NPB, it is unreliable for detecting people with only one functional copy of the ASM gene referred to as 'carriers.' In addition, the test will show decreased ASM activity yet cannot 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 many people with ASM deficiency. About 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 must first be identified in people affected before DNA carrier testing can be performed for family members. Recently, a 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 several laboratories in America.
Molecular genetic testing is available at this time on a commercial basis for NPB at several laboratories. Healthcare providers should contact laboratory personnel to arrange such testing for interested people. Once a person 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 low and variable condition that some healthcare providers might not recognize. Specialists who suspect NPC in a person can diagnose by taking a skin biopsy, growing cells in the laboratory, and studying the cell's ability to transport and store cholesterol. The transport of cholesterol in cells is studied by measuring the 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, only two laboratories in America perform diagnostic testing about 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 is not permitted to discuss testing with either patients or their family members directly, so the person's healthcare provider must contact the laboratory. The healthcare provider will be given directions for collecting the sample and 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 and in the second NPC gene, referred to as 'NPC2.' In all, for 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. There are so many unique mutations in these genes; however, as well as people with classic NPC in whom mutations have not been identified, 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 are known. Genetic testing has also been used better to identify the carrier risk for known carrier partners.
three laboratories in the United States perform genetic testing for NPC. One is in Gaithersburg, MD. Another laboratory is the Mayo Clinic Genetic Laboratory. The third laboratory performing NPC genetic testing 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 yet discovered a form of treatment for NPA. Supportive forms of treatment can assist in managing 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 1990s, research into therapies for NPB has progressed rapidly. The Mount Sinai School of Medicine is researching 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 occurs 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 also been tested on mice and is effective for NPB. The therapy has also succeeded in other lysosomal storage diseases, including 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 replace a defective gene with healthy genes. Constructive results of this form of therapy have been obtained with individual cells. However, testing about Niemann-Pick disease and mice is only beginning.
Supportive forms of treatment may also assist in managing symptoms related to NPB. 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 the 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 insurers are hesitant to pay for the medication for people with NPC without U.S. FDA approval. The FDA 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 made up of 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 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...
Thomas C. Weiss is a researcher and editor for Disabled World. Thomas attended college and university courses earning a Masters, Bachelors and two Associate degrees, as well as pursing Disability Studies. As a Nursing Assistant Thomas has assisted people from a variety of racial, religious, gender, class, and age groups by providing care for people with all forms of disabilities from Multiple Sclerosis to Parkinson's; para and quadriplegia to Spina Bifida.
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