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Sanfilippo syndrome
medical conditions

Sanfilippo syndrome

Explore the available health information, treatment context, and integrative evidence for Sanfilippo syndrome.

Background
  • Sanfilippo syndrome is an inherited disease that belongs to a group of diseases called mucopolysaccharidoses (MPS). Specifically, it is known as MPS type 3. Mucopolysaccharides are complex sugar molecules that are constantly used and broken down in the body. In 1963, Dr. Sylvester Sanfilippo was one of the first doctors to describe Sanfilippo syndrome.
  • In individuals with Sanfilippo syndrome, one of the enzymes that break down heparan sulfate, a carbohydrate, or complex sugar molecule, that inhibits blood clotting, is missing or malfunctioning. This causes heparan sulfate to buildup to abnormally high levels in lysosomes, which are the compartments in the cell responsible for breaking down and disposing of cell waste. Waste products that buildup in lysosomes are excreted in the urine, so individuals with Sanfilippo syndrome tend to have high levels of heparan sulfate in their urine.
  • Because of the buildup of heparan sulfate, cells do not function properly. Symptoms of Sanfilippo syndrome include problems with the heart, bones, joints, and lungs. As the disease progresses, this buildup of heparan sulfate in nerve cells causes serious problems resulting from the failure of the nervous system.
  • It is estimated that Sanfilippo syndrome affects one out of every 80,000 births. Males and females are affected in equal numbers. The disease may not be apparent at birth. Signs and symptoms progress with age as heparan sulfate accumulates and damages cells and organs. Most people with Sanfilippo syndrome live into their teenage years. Some patients live longer, while others with severe forms die at an earlier age from complications.
  • There are four types of Sanfilippo syndrome: types A, B, C, and D. Each type is caused by mutations in one of the four genes that provide instructions for making enzymes involved in breaking down heparan sulfate. Depending on the type of Sanfilippo syndrome, the mutation could occur in the gene for heparan sulfate sulfatase (type A), alpha-N-acetylglucosaminidase (type B), acetyl-CoA alpha-glucosaminide N-acetyltransferase (type C), or N-acetylglucosamine 6-sulfatase (type D).
Risk Factors and Causes
  • General: Sanfilippo syndrome results when the enzymes needed to break down heparan sulfate are missing or defective.
  • Genetic mutations: Each of the four types of Sanfilippo syndrome is caused by a mutation in a different gene responsible for encoding or providing instructions for making a specific enzyme that breaks down heparan sulfate. Mutations in the heparan sulfate sulfatase gene cause type A Sanfilippo syndrome. Mutations in the alpha-N-acetylglucosaminidase gene cause type B Sanfilippo syndrome. Mutations in the acetyl-CoA alpha-glucosaminide N-acetyltransferase gene cause type C Sanfilippo syndrome. Mutations in the N-acetylglucosamine 6-sulfatase gene cause type D Sanfilippo syndrome.
  • Inheritance: Sanfilippo syndrome is an inherited disorder passed down in families as an autosomal recessive trait. Individuals have two copies of most genes (one inherited from the father and one from the mother). In a recessive genetic disorder, both copies of a certain gene need to be defective for the condition to occur.
  • People who have only one mutated gene usually do not show symptoms of the disease, but are called "carriers" because they may pass the mutated gene to their children. If only one parent is a carrier, none of the children will have Sanfilippo syndrome, but each child has a 50% chance of inheriting one mutated gene and of being a carrier.
  • If both parents are carriers, then each child has a 50% chance of also being a carrier, a 25% chance of inheriting two copies of the defective gene and having the disease, and a 25% chance of not inheriting either mutated gene and not having the disease.
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  • Because Sanfilippo syndrome is inherited, the only known risk factor is a family history of the disorder. Certain populations are known to have a higher incidence of Sanfilippo syndrome, such as the populations of Britain and the Cayman Islands.
Signs and Symptoms
  • General: The symptoms of Sanfilippo syndrome generally appear between the ages of two and six. The majority of patients develop symptoms by four years of age. The disorder usually progresses slowly.
  • Developmental problems: Initially the child appears normal, but then starts to fall behind in developmental areas such as walking and talking. Behavioral problems are common and may include hyperactivity, aggressiveness, and restlessness. Early progress in language and understanding is lost as a severe learning disability develops. Delayed development is followed by deteriorating mental status. From age five to 10, the difficult behavior and hyperactivity progress.
  • The child may have normal growth during the first few years of life, but the final height is below average. After age 10, people with Sanfilippo syndrome physically slow down, gradually lose movement skills, balance, and coordination, and develop tremors.
  • Physical features: There may be physical features such as an enlarged head, full lips, and heavy eyebrows that meet in the middle of the face above the nose. Bone density is usually lower than normal. However, many children with Sanfilippo syndrome do not have these symptoms.
  • Other: Other symptoms may include diarrhea, incontinence, speech and hearing impairment, constant runny nose, hernia, heart disease, depression, pain, and stiff joints that may not extend fully. Tumors may form on the retina (i.e., the back of the eye).
Diagnosis
  • Audiogram: An audiogram, or hearing test, may help diagnose hearing loss. During an audiogram, the patient wears headphones and is exposed to various sounds that have different pitches and frequencies. The patient is asked to identify each time a sound is heard. The audiologist may also say various words to evaluate the patient's hearing ability.
  • Biopsy: Once tumors are identified, a biopsy may be performed to determine whether they are cancerous. A small tissue sample is taken from the patient and analyzed under a microscope to determine whether cancerous cells are present.
  • Blood tests: Blood can be drawn, or samples of cells from the skin may be taken and grown, to test for abnormal heparan sulfate-related enzyme levels.
  • Echocardiogram: An echocardiogram, which uses sound waves to create a moving picture of the heart, can be used to test for abnormal heart rhythms.
  • Eye exam: During an eye exam, a slit lamp test may be performed to determine whether there are tumors on the retina. The slit lamp is a microscope with a light that helps the eye doctor observe the eye under high magnification. The doctor is able to see the front and the back of the eye.
  • Genetic testing: Genetic testing is available only through research institutions studying the disorder. A sample of the patient's blood is analyzed in a laboratory for the presence of a mutated gene. A total of 62 mutations have now been identified for Sanfilippo type A, and 86 mutations for Sanfilippo type B. For these types, many of the reported mutations are unique, making screening in the general population difficult. However, examination of DNA from patients with Sanfilippo type A has revealed a high incidence of particular mutations of different geographical origins, which may be beneficial for future diagnoses of Sanfilippo type A.
  • If there is a family history of Sanfilippo syndrome, prenatal genetic testing may be offered to determine whether a patient's fetus has the disorder. However, testing is not widely available, and prenatal genetic testing for Sanfilippo syndrome is controversial because it cannot predict the severity of the disorder. In addition, prenatal genetic testing carries serious risks, including miscarriage. Therefore, patients should discuss the potential health benefits and risks associated with these procedures with a healthcare professional or genetic counselor before making any medical decisions.
  • Nerve conduction study: A nerve conduction study is used to measure how quickly nerves are able to send electrical signals. To perform this test, metal electrodes are attached to the skin. One electrode is placed over a nerve and another is placed over the muscle controlled by that nerve. Clinicians can deliver a mild shock to the nerve, and measure the amount of time it takes the muscle to respond to the impulse. If the response times are slow, it may indicate a nervous system disorder.
  • Physical exam: A physical exam may show signs of liver and spleen swelling caused by the accumulation of heparan sulfate. There may be evidence of seizures, swallowing difficulties, and mental disabilities. Individuals with Sanfilippo syndrome are shorter than average when fully grown. Other features may include an enlarged head, full lips, and heavy eyebrows that meet in the middle of the face above the nose.
  • Urine test: Because people with Sanfilippo syndrome cannot break down heparan sulfate, it builds up in cells and is excreted in the urine.
  • X-rays: X-rays of the bones may be taken because Sanfilippo syndrome patients generally have a lower than normal bone density.
Complications
  • General: Complications associated with Sanfilippo syndrome all result from the gradual breakdown of the nervous system.
  • Impaired movement: Patients with Sanfilippo syndrome have difficulty walking due to impaired function of the nerves that control leg muscles. They often experience a loss of balance and coordination. The ability to move the arms or hands is usually also impaired, and it is common for patients to exhibit muscle spasms and loss of feeling in the hands and feet.
  • Nerve degeneration: Patients with Sanfilippo syndrome experience a progressive degeneration of nerve tissue. The nerve cells lose their myelin sheath, which is a covering that helps nerve cells conduct impulses. This loss causes the nerves to be unable to control muscles throughout the body, and the muscles eventually begin to waste away, or atrophy, due to lack of use.
  • Speech and swallowing problems: Some patients may begin to have difficulty speaking and may exhibit slurring or slowness of speech, caused by loss of muscle function around the mouth and in the tongue. For the same reason, swallowing may be difficult, which may cause choking and aspiration of food and liquid.
  • Other: Other complications observed in individuals with Sanfilippo syndrome include blindness, heart disease, arthritis, and skin blistering.
Treatment
  • General: There is currently no known cure for Sanfilippo syndrome. Treatment instead focuses on the management of symptoms and the prevention of complications. Most of the symptoms are caused by neurological degeneration, which cannot be reversed.
  • Assisted mobility devices: Most patients with Sanfilippo syndrome lose the ability to walk. A cane, leg braces, walker, or wheelchair may be required if walking becomes painful or difficult as a result of bone, tendon, ligament, or muscle problems.
  • Behavioral therapy: Behavioral therapy may benefit Sanfilippo syndrome patients who have behavioral problems. Several different types of behavioral therapy are available to improve communication and social skills, and to improve learning abilities and adaptive behaviors. The specific type of behavioral therapy used depends on the person's individual needs because people experience a wide range of symptoms that require specific treatment.
  • Diet: Dietary management is important for Sanfilippo syndrome patients with swallowing difficulties in order to promote physical development and keep the potential for mobility high. When the body is deprived of calories and protein, it begins to feed on its own muscles for nourishment. For this reason, maintaining adequate nutrition is very important. A speech pathologist may be able to identify whether certain foods may be particularly hazardous to a patient. To prevent choking and aspiration, solid food may be pureed and liquids may be thickened for individuals with Sanfilippo syndrome.
  • Occupational therapy: Patients with intellectual disabilities (formerly called mental retardation) may benefit from occupational therapy. During therapy sessions, a therapist may help the child learn to perform activities of daily living, such as feeding, dressing, and communicating with others. Some patients work with therapists who specialize in disorders accompanied by intellectual and physical disabilities. Parents and caregivers can ask their child's pediatrician to recommend a therapist.
  • Physical therapy: Patients with Sanfilippo syndrome may benefit from seeing a physical therapist. A physical therapist can help patients maintain muscle tone and keep muscles strong and flexible by performing different exercises.
  • Speech-language therapy: Some patients with Sanfilippo syndrome may benefit from speech-language therapy if they have intellectual disabilities or if they develop communication skills more slowly than normal children. Qualified speech-language professionals (SLPs) work with patients one-on-one, in small groups, or in classrooms to help patients improve speech, language, and communication skills. Programs are tailored to patients' individual needs. Speech pathologists use a variety of exercises to improve the patient's communication skills. Exercises typically start off simple and become more complex as therapy continues. For instance, the therapist may ask the patient to name objects, tell stories, or explain the purpose of an object.
  • Future treatments: Mutated gene carrier detection, the development of replacement enzymes, and the possibility of gene therapy are all promising future treatments. Various experimental methods have been used to try to replace the missing enzymes, but so far none have shown any significant long-term benefit. Bone-marrow and cord-blood transplantation have been considered successful in some cases, but have shown disappointing results overall. Relatively few individuals qualify for such high-risk procedures.
Prevention
  • If a person has a family history of Sanfilippo syndrome, genetic testing may be performed to determine whether mutations are present that affect any of the four genes responsible for heparan sulfate degradation. Although carriers do not have the disease, they can pass a copy of the mutated gene to their children.
  • Prenatal DNA testing may be performed if there is a family history of Sanfilippo syndrome. Diagnosis during pregnancy is possible using chorionic villus sampling (CVS) at about 11 weeks or amniocentesis at around 14 weeks. However, there are health risks associated with prenatal genetic testing, including miscarriage.
  • Before and after genetic testing, individuals should meet with a genetic counselor, who can help them understand the risks of having a child with Sanfilippo syndrome. A genetic counselor can also explain the different types of genetic tests, including their potential risks and benefits. These counselors can help patients understand and interpret the test results.
  • Patients diagnosed with Sanfilippo syndrome should undergo regular checkups with their doctors in order to reduce the risk of developing complications.
References

Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

  • Aydin M, Akarsu S, Kabakus N, et al. Mucopolysaccharidosis IIIB, cerebral vasculopathy and recurrent subdural hematoma. Indian Pediatr. 2006 May;43(5):437-40. View Abstract
  • Beesley CE, Jackson M, Young EP, et al. Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB). J Inherit Metab Dis. 2005;28(5):759-67. View Abstract
  • Hrebícek M, Mrázová L, Seyrantepe V, et al. Mutations in TMEM76* cause mucopolysaccharidosis IIIC (Sanfilippo C syndrome). Am J Hum Genet. 2006 Nov;79(5):807-19. View Abstract
  • Moog U, van Mierlo I, van Schrojenstein Lantman-de Valk HM, et al. Is Sanfilippo type B in your mind when you see adults with mental retardation and behavioral problems? Am J Med Genet C Semin Med Genet. 2007 Aug 15;145(3):293-301. View Abstract
  • National Institutes of Health Office of Rare Diseases. . Accessed March 23, 2008.
  • National MPS Society. . Accessed March 23, 2008.
  • Natural Standard: The Authority on Integrative Medicine. Copyright © 2008.
  • Yogalingam G, Hopwood JJ. Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum Mutat. 2001 Oct;18(4):264-81. View Abstract