Mucopolysaccharidosis

• Mucopolysaccharidosis (MPS) is a group of related lysosomal storage diseases. Lysosomes are compartments in cells that break down molecules and remove waste products from cells. Normally, 11 different enzymes in the lysosomes break down sugars called glycosaminoglycans, also known as mucopolysaccharides. In MPS, glycosaminoglycans are not broken down because of a deficiency in one of the 11 enzymes. As a result, the glycosaminoglycans accumulate in the cells and cause tissue damage.
• Different types of MPS are classified by the enzymes that are absent or deficient. To date, seven types of MPS have been reported, MPS I, II, III, IV, VI, VII, and IX.
• All types of MPS are inherited and share very similar physical symptoms. The physical symptoms may include thickening of lips and skin, enlarged tongue and mouth, abnormal bone size and shape, joint pain and stiffness, and short stature. Neurological symptoms are present in some types of MPS and may vary in severity.
• It is estimated that in the United States, one in 25,000 births are affected by some form of MPS. MPS III, also called Sanfilippo syndrome, is one of the more common types, while MPS VII is very rare. Lifespan of a patient with MPS varies depending on the severity and type of disease but it is possible for a person with a mild form of MPS to live into adulthood.
• There is currently no known cure for MPS. Treatment aims to relieve and manage symptoms in order to improve and prolong life. Physical therapy and surgery may be useful for correcting abnormalities. Therapies that aim to replace the deficient enzymes may help improve pain and neurological symptoms.

• Mucopolysaccharidosis (MPS) is a disorder caused by genetic errors, or mutations, in any of the genes that produce the enzymes responsible for glycosaminoglycan degradation. Because MPS is inherited, a family history of the disorder is the primary risk factor for MPS.
• Autosomal recessive inheritance: Most types of mucopolysaccharidosis (MPS) are inherited as autosomal recessive traits. MPS II or Hunter syndrome is the only form of MPS that is X-linked dominant. A person must inherit two copies of the genetic mutation (one copy from each parent) to develop a recessive form of MPS. People who inherit a mutation from only one parent are called "carriers," and they may pass the mutation to their children.
• If only one parent has one copy of the mutated gene, then each child will have a 50% chance of inheriting one mutated gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two mutated genes, a 50% chance of inheriting only one mutation, and a 25% chance of inheriting neither of the mutations.
• If one parent has MPS and the other parent does not carry the trait, then all of the children will be carriers. If one parent has MPS and the other parent is a carrier, then each child has a 50% chance of having MPS and a 50% chance of being a carrier. If both parents have MPS, then all of their children will also have MPS.
• X-linked dominant inheritance: MPS II or Hunter syndrome is an X-linked dominant inherited genetic condition. Normal individuals have two copies of most genes (one inherited from the father and one from the mother). A person needs to inherit only one copy of the defective gene to develop a dominant disease. A deficiency or mutation in the enzyme iduronate sulfatase, which is located on the X chromosome, may cause MPS II.
• Females have two copies of the X chromosome, but males have one X chromosome and one Y chromosome. Males inherit an X chromosome from the mother and a Y chromosome from the father, so a male can only inherit MPS II from the mother. Therefore, a female needs to inherit two mutant copies to develop MPS II (one from each parent), whereas a male only needs to inherit one mutant copy to develop the condition. MPS II is more common in males that females. Females who inherit only one mutant copy are called "carriers." Female carriers may exhibit some mild symptoms.

• General: Mucopolysaccharidosis (MPS) is a group of diseases that are also classified as lysosomal storage diseases. Lysosomes are compartments in the cell that contain various enzymes that degrade (break down) molecules. In MPS, glycosaminoglycans or mucopolysaccharides are not degraded.
• Glycosaminoglycans are polysaccharides, or long-chain sugars, that normally help the growth of bone, skin, tendons, connective tissues, and eyes. Glycosaminoglycans are also typically found in the fluid that surrounds joints. When they are not broken down, glycosaminoglycans may cause progressive cellular damage.
• Normally, a gene (specific region of DNA) provides the body with instructions on how to make an enzyme. There are 11 enzymes involved in the breakdown of glycosaminoglycans. A deficiency or absence of any one of the enzymes may cause MPS, but only seven have been found to occur in humans. The type of MPS is classified by the enzyme that is deficient. The most likely pattern of inheritance is autosomal recessive although some types of MPS may be inherited as an X-linked dominant trait.
• MPS I: MPS I is caused by a deficiency of the enzyme alpha-L-iduronidase.
• MPS II: MPS II is caused by a deficiency of the enzyme iduronate sulfatase. This is the only form of MPS that is X-linked dominant.
• MPS III: MPS III is caused by a deficiency of an enzyme that breaks down heparan sulfate. There are four subtypes of MPS III, and they are types A, B, C, and D. Type A affects the enzyme heparan N-sulfatase, B affects alpha-N-acetylglucosaminidase, C affects acetyl-CoA alpha-glucosaminide acetyltransferase, and D affects N-acetylglucosamine 6-sulfatase.
• MPS IV: MPS IV is caused by a deficiency of an enzyme that breaks down keratin sulfate. There are two subtypes of MPS IV. Type A affects the enzyme N-acetylgalactosamine 6-sulfatase and type B affects beta-galactosidase.
• MPS VI: MPS VI is caused by a deficiency of the enzyme N-acetylgalactosamine 4-sulfatase.
• MPS VII: MPS VII is caused by a deficiency of the enzyme beta-glucuronidase.
• MPS IX: MPS IX is caused by a deficiency of the enzyme hyaluronidase.
• Autosomal recessive inheritance: Most types of mucopolysaccharidosis (MPS) are autosomal recessive disorders that are inherited at birth. MPS II or Hunter syndrome is the only form of MPS that is X-linked dominant. In a recessive genetic disorder, a person must inherit two copies of the genetic mutation (one copy from each parent) to develop MPS. People who inherit a mutation from only one parent are called "carriers," and they may pass the mutation to their children.
• If only one parent has one copy of the mutated gene, then each child will have a 50% chance of inheriting one mutated gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two mutated genes, a 50% chance of inheriting only one mutation, and a 25% chance of inheriting neither of the mutations.
• If one parent has MPS and the other parent does not carry the trait, then all of the children will be carriers. If one parent has MPS and the other parent is a carrier, then each child has a 50% chance of having MPS or of being a carrier. If both parents have MPS, then all of their children will also have MPS.
• X-linked dominant inheritance: MPS II or Hunter syndrome is an X-linked dominant inherited genetic condition. Normal individuals have two copies of most genes (one inherited from the father and one from the mother). In a dominant genetic disorder, only one copy of a certain gene needs to be defective for the condition to manifest. It has been shown that a deficiency or mutation in the enzyme iduronate sulfatase, which is located on the X chromosome, may cause MPS II.
• Females have two copies of the X chromosome, but males have one X chromosome and one Y chromosome. Males inherit an X chromosome from the mother and a Y chromosome from the father, so a male can only inherit MPS II from the mother. A female needs to inherit two mutant copies to develop MPS II (one from each parent), whereas a male only needs to inherit one mutant copy to develop the condition. MPS II is more common in males that females. Females who inherit only one mutant copy are called "carriers." Females who are carriers may exhibit some mild symptoms.
• Random occurrence: It is unknown whether MPS can occur as the result of a spontaneous genetic mutation with no family history of the disease.

• Each type of mucopolysaccharidosis differs in clinical presentation and has varying degrees of severity. All types have a period of normal growth that is followed by a decline in physical and mental functioning.
• Common physical symptoms include thickened lips and skin, an enlarged tongue and mouth, abnormal bone size and shape, joint pain and stiffness, corneal clouding, hernias, and short stature. Organs may also be enlarged, specifically the liver and spleen.
• Neurological symptoms may occur in some types of MPS. Decreased intellectual capacity, hyperactivity, delirium, and aggressive behavior are often clinical signs.
• Effects on breathing function include sleep apnea, obstructive airway disease, chronic respiratory infections, enlarged tonsils and adenoids, and noisy and difficult breathing.
• Heart abnormalities may be more common in some types of MPS than others. These abnormalities may consist of valve defects, thickening and stiffening of the heart wall, and narrowing of blood vessels.

• General: Mucopolysaccharidosis may be suspected after a thorough physical examination. Common physical symptoms may include thickened lips and skin, enlarged tongue and mouth, abnormal bone size and shape, and short stature. An elevated level of glycosaminoglycans may also be detected in the urine indicating mucopolysaccharidosis. A urine test does not distinguish between the different types of mucopolysaccharidosis.
• DNA testing: DNA testing may be performed to confirm and classify mucopolysaccharidosis. Each type of MPS has a known mutation that is specific to the type of disease. In cases of a family history of MPS, genetic testing may also be used to identify a carrier. If MPS is suspected, a cytogenetic test may be performed to confirm a diagnosis. A sample of the patient's blood is taken and analyzed in a laboratory for a defect in any of the 11 enzymes involved in the breakdown of glycosaminoglycans. The 11 enzymes that may be affected in MPS are alpha-L-iduronidase, iduronate sulfatase, alpha-N-acetylglucosaminidase, heparan N-sulfatase, acetyl-CoA alpha-glucosaminide acetyltransferase, acetylglucosamine 6-sulfatase, acetylgalactosamine 6-sulfatase, beta-galactosidase, N-acetylgalactosamine 4-sulfatase, beta-glucuronidase, and hyaluronidase.
• Enzyme testing: An enzyme assay may be used to make a definitive diagnosis of the type of MPS based upon the levels of the 11 enzymes involved in glycosaminoglycan breakdown. Enzyme activity is measured from a tissue or blood sample of leukocytes, fibroblasts, or serum that is combined with a substrate that is particular to the target enzyme. The target enzyme can be alpha-L-iduronidase, iduronate sulfatase, alpha-N-acetylglucosaminidase, heparan N-sulfatase, acetyl-CoA alpha-glucosaminide acetyltransferase, acetylglucosamine 6-sulfatase, acetylgalactosamine 6-sulfatase, beta-galactosidase, N-acetylgalactosamine 4-sulfatase, beta-glucuronidase, or hyaluronidase.
• Prenatal testing: If there is a family history of MPS, prenatal testing may be performed to determine if the fetus has the disorder. Amniocentesis and chorionic villus sampling (CVS) can diagnose MPS. However, because there are serious risks associated with these tests, patients should discuss the potential health benefits and risks associated with these procedures with a medical professional and/or genetic counselor.
• During amniocentesis, a long, thin needle is inserted through the abdominal wall into the uterus and a small amount of amniotic fluid is removed from the sac surrounding the fetus. Cells in the fluid are then analyzed for normal and abnormal chromosomes. This test is performed after 15 weeks of pregnancy. The risk of miscarriage is about one in 200 to 400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.
• During CVS, a small piece of tissue (chorionic villi) is removed from the placenta between the ninth and 14th week of pregnancy. CVS may be performed through the cervix or through the abdomen. The cells in the tissue sample are then analyzed for the mutations responsible for MPS. Miscarriage occurs in about 0.5% to 1% of women who undergo this procedure.

• General: Patients should be continually followed by their physician to be assessed for declining physical and mental functioning. Depending on the type of mucopolysaccharidosis (MPS), patients may need to be evaluated more often than others due to differences in disease progression and severity.
• Cardiovascular: Common heart abnormalities may include valve defects, thickening and stiffening of the heart wall, and narrowing of blood vessels. Complications of heart abnormalities are cardiovascular collapse and death if not corrected. Surgery and prescription medications may be useful in preventing complications.
• Respiratory: Effects on breathing function include sleep apnea, obstructive airway disease, chronic respiratory infection, enlarged tonsils and adenoids, and noisy and difficult breathing. Chronic respiratory infections can lead to pneumonia, which can be life-threatening if untreated. Enlarged adenoids and tonsils may contribute to difficulty breathing and sleep apnea.
• Skeletal: Abnormal bone size and shape and joint pain and stiffness may lead to decreased mobility and quality of life. Bone abnormalities may compress nerves and press on organs, leading to inhibition of normal neurological function, organ function, and even paralysis.

• General: Currently, there is no known cure for any form of mucopolysaccharidosis (MPS), but there are treatments available to manage symptoms, prevent complications, and improve quality of life. Physical therapy may be helpful in the prevention and treatment of joint pain and stiffness that is common in all types of MPS.
• Bone marrow transplant: Some types of MPS have had limited success with bone marrow transplantation. The use of bone marrow transplantation may be beneficial when performed at an early age in MPS I. A bone marrow transplant may provide cells that produce normal, functioning enzymes that may be otherwise deficient in MPS. The use of early bone marrow transplants may help to delay intellectual disability (formerly mental retardation) and improve other symptoms, but does not reverse damage that has already happened. A proper donor must be found to perform a bone marrow transplant, and this procedure is considered high-risk due to possible complications.
• Enzyme replacement: Recombinant enzyme products are available for the treatment of specific types of MPS. Depending on the enzyme that is deficient or missing, the appropriate enzyme replacement may help in reducing some of the symptoms associated with whatever disease is being treated. Research has shown that neurological symptoms and pain may improve with enzyme replacement therapy.
• Physical therapy: Patients with MPS may benefit from seeing a physical therapist. A physical therapist can help patients maintain muscle tone and keep muscles strong and flexible through performing different exercises. A speech therapist may help a patient retrain the tongue and facial muscles to improve speech.
• Surgery: Various types of surgery have been performed depending on the symptom being treated. For patients with sleep apnea and obstructive airway disease, the removal of tonsils and adenoids may be beneficial in improving breathing. Corneal transplants may be useful for treating patients with corneal clouding. Surgery has also been used to relieve compression on nerves and the spinal cord, repair hernias, fix heart abnormalities, and to place shunts to allow for drainage of cerebrospinal fluid.

Note
: Currently, there is a lack of evidence on the use of integrative therapies for the treatment or prevention of mucopolysaccharidosis. The therapies listed below have been studied for related conditions such as joint pain, sleep apnea, and chronic respiratory infections. These integrative therapies should be used only under the supervision of a qualified healthcare provider and should not be used in replacement of other proven therapies or preventive measures.

A

Strong scientific evidence

• Andrographis paniculata

  : Andrographis paniculata has traditionally been used as a treatment for fever and infectious illnesses in a number of Asian medical systems. Based on this historical use, it has more recently become popular in Western countries as a treatment for upper respiratory illness. Clinical trials, mostly done on the standardized product Kan Jang® (Swedish Herbal Institute), collectively suggest that this herb is effective in reducing symptom severity and duration in upper respiratory tract infections both in children and adults, if started within 36-48 hours of the onset of symptoms. Three cases of anaphylactic reactions, including one case of shock, have been reported to the World Health Organization Collaborating Center for International Drug Monitoring as of June 2003. Avoid with infertility or patients actively trying to conceive. Use cautiously with diabetes, bleeding disorders, and high or low blood pressure. Use cautiously with blood sugar-altering medications, warfarin or other blood thinning medications, and blood pressure-altering medications. Avoid if pregnant or breastfeeding.

• Unclear or conflicting evidence
  :
• Acupressure, Shiatsu
  : Limited study reports that acupressure may provide early prevention and treatment for sleep apnea. Larger, well-designed studies are needed before conclusions can be drawn. Patients with known or suspected sleep apnea should consult with a licensed healthcare professional. With proper training, acupressure appears to be safe if self-administered, or administered by an experienced therapist. Serious long-term complications have not been reported, according to scientific data. Hand nerve injury and herpes zoster ("shingles") cases have been reported after shiatsu massage. Forceful acupressure may cause bruising.
• Aromatherapy
  : Early study suggests pre-mature newborns with sleep apnea may benefit from aromatherapy. However, more data are needed before definitive recommendations can be made. Essential oils should be administered in a carrier oil to avoid toxicity. Avoid if the patient has a history of allergic dermatitis. Use cautiously if driving/operating heavy machinery. Avoid consuming essential oils. Avoid direct contact of undiluted oils with mucous membranes. Use cautiously if pregnant.
• Physical therapy
  : Physical therapy has been used to treat a variety of joint problems, including chronic ankle instability, clubfoot (a birth defect of the ankle/foot), and impingement syndrome. Most studies stress early intervention to speed recovery, although studies are lacking that compare early intervention to later intervention, spontaneous healing, and other modalities, including sham treatments. Better-designed trials are needed before a firm recommendation can be made. Not all physical therapy programs are suited for everyone, and patients should discuss their medical history with a qualified healthcare provider before beginning any treatments.
• Based on the available literature, physical therapy appears generally safe when practiced by a qualified physical therapist. However, complications are possible. Treatment options should be considered carefully. Physical therapy may aggravate pre-existing conditions. Persistent pain and fractures of unknown origin have been reported. Physical therapy may increase the duration of pain or cause limitation of motion. Pain and anxiety may occur during the rehabilitation of patients with burns. Both morning stiffness and bone erosion have been reported in the literature, although causality is unclear. Erectile dysfunction has also been reported. Physical therapy has been used during pregnancy, specifically to treat women with pelvic girdle pain, and at three, six, and 12 months postpartum. Reports of major adverse effects are lacking in the available literature, but caution is advised nonetheless. All therapies during pregnancy and breastfeeding should be discussed with a licensed obstetrician/gynecologist before initiation.
• Stinging nettle
  : Stinging nettle has historically been used in several different forms to treat pain of varying origins. However, there is a lack of available scientific evidence to confirm this use and additional study is needed. Avoid if allergic or hypersensitive to nettle, the Urticaceae family, or any ingredient of nettle containing products. Use cautiously in patients with diabetes, bleeding disorders, and low sodium levels in the blood. Use cautiously with diuretics and anti-inflammatory drugs. The elderly should also use nettle cautiously. Avoid if pregnant or breastfeeding.

• General: Because mucopolysaccharidosis (MPS) is an inherited genetic condition, there is currently no known way to prevent it. However, genetic screening and counseling may reduce the risks of having children with MPS.
• Genetic testing and counseling: Individuals with a family history of MPS or who have MPS may meet with genetic counselors to discuss the risks of having children with the disease.
• Known carriers of MPS may undergo genetic counseling before they conceive a child. Genetic counselors can explain the options and the associated risks of various tests, including pre-implantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS).
• Pre-implantation genetic diagnosis (PGD) may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for MPS and only the embryos that are free of the MPS mutations may be implanted. This procedure is considered controversial.