Sanfilippo syndrome belongs to a group of diseases called mucopolysaccharidoses (MPS).
Another name for Sanfilippo syndrome is MPS III.
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How does Sanfilippo syndrome (MPS III) happen?
Sanfilippo syndrome is an inherited disease of metabolism. It happens because the body is unable to correctly break down long chains of sugar molecules called glycosaminoglycans (often shortened to GAGs). [ Note: these sugars were originally called mucopolysaccharides. ] This happens because there is a single missing or deficient enzyme that is needed to break down the sugars
Both parents, almost always unknowingly, carry a defective gene that controls production of the critical enzyme. When that happens, each of their children has a one in four chance of developing Sanfilippo Syndrome. Parents of Sanfilippo children frequently have more than one child before finding that they carry the defective gene, and that one or more of their children have the syndrome. A popular estimate of the incidence of Sanfilippo syndrome is that it occurs once in every 70,000 births. There is no doubt that the frequency of the disease varies among different populations with different genetic makeup. Populations of Northern European origin are said to have a higher frequency of the disease than other populations.The characteristics of Sanfilippo syndrome
To date four different enzyme deficiencies have been found to cause Sanfilippo Syndrome and so the condition is described as type A, B, C, or D. These enzymes are:
| Type | Missing enzyme | Gene location |
|---|---|---|
| Sanfilippo A | Heparan-N-sulphatase | 17q25.3 |
| Sanfilippo B | a-N-Acetylgucosaminidase | 17q21 |
| Sanfilippo C | AcetylCoA:N-acetyltransferase | 8p11-q13 |
| Sanfilippo D | N-Acetylglucosamine 6-sulphatase | 12q14 |
Types C and D are the rarest, estimated to be <5% of cases each. In Western countries, at least, Type A is the most common (about 60% of cases), with Type B next(~30%), and Types C and D the least common.
- Kevin has Sanfilippo type C and Lucas on the right has Sanfilippo type B
There is usually very little difference in the kinds of effects of the four types of the disorder. There have been some very mild cases of each form where the affected individuals have remained relatively healthy into adult life. The latest understanding is that some people seem to produce some enzyme activity which helps to slow down the progression of the disorder whilst those with more severe symptoms appear to have no enzyme activity (or function) at all. It is important to understand that all those with Sanfilippo syndrome have the same condition, even if some have a milder form.
The common factor is that all four types result from a buildup of heparan sulfate in the cells. More about the differences in the types below.
There are four main types of Sanfilippo syndrome. Which type a person has depends on which enzyme is affected.
The frequency (prevalence) of Sanfilippo syndrome as a whole is difficult to estimate, even in specific population groups. To go with that, the estimates of the relative frequency of the four types is also difficult to estimate. The different types of the disease might be accurately diagnosed and identified differently (because the average age of diagnosis and the average age of onset of severe symptoms differs among the types).
•Sanfilippo type A is considered the most severe form of the disease on the average. Persons with this type are missing or have an altered form of an enzyme called heparan N-sulfatase. About 70% of Sanfilippo children in the United States and Western Europe have Type A.
•Sanfilippo Type B occurs in about 20-25% of cases (again in the U.S. and Western Europe). Children with Type B live longer (on the average) than those with Type A, but they are impacted in the same way.
•Type C is thought by some to be the rarest of the four types, occurring in less than 5% of cases. Persons with Type C have (on the whole) a later onset of symptoms, a longer life expectancy, and a somewhat milder course of the disease, However, as with Type B, the disease does ultimately progress and there is a shortened life expectancy with progressive physical and mental deterioration occurring during the person’s life span.
•Sanfilippo D occurs when a person is missing or doesn’t not produce enough N-acetylglucosamine 6-sulfatase. Type D also is estimated to occur in around 1-3% of the cases, but some feel that estimate is high, and that Type D is much rarer than that.
There is some evidence that in Greece and surrounding European and Asian countries, Sanfilippo B may represent a considerably higher percentage of Sanfilippo cases and Type A a correspondingly lower percentage.
All four types of Sanfilippo syndrome are associated with brain involvement that causes progressive brain and nervous system damage. There is also developmental regression and deterioration of intellectual functioning. The child regresses behaviorally and mentally, going back to younger and younger behavior as the brain cells are impacted. There are many and varying abnormalities in behavior. Children with Sanfilippo syndrome have a shortened life expectancy. There is more detail lower on the page.
Other symptoms include:
•Behavioral problems
•Coarse facial features
•Diarrhea
•Full lips
•Heavy eyebrows that meet in the middle of the face above the nose
•Sleep difficulties
•Stiff joints that may not extend fully
•Walking problems
There’s a lot of variation in what MPS3 kids are like at every age. However, certain characteristics are common. While the buildup of waste products affects cells all through the body, the most severe damage for Sanfilippo children is to the brain. That damage affects everything about the body and about the intellect and personality of the child as well.
Most Sanfilippo children appear normal at birth and for the first one to three years of life. Hearing loss is a common first diagnosis. Many are diagnosed with autism in the early years because of slow or nonexistent speech. They also show varying degrees of aggressive behavior and poorly controlled temper tantrums. At the same time, many Sanfilippo kids also have vibrant, happy personalities and many love to sing and dance.
The waste product builds up in the brain over the years, bringing with it a gradual loss of every ability. One of the first things lost is speech. Some Sanfilippo children never speak. Nearly all children lose most speech and much of their understanding of speech by the age of 7 or 8. Many children go through a stage of hyperactivity, where they are unable to attend to any single task for more than a few seconds. Children will often develop a fixed pattern of actions that they repeat over and over (for example, going through the house doing a fixed set of things, then repeating the cycle multiple times.) Change is often very difficult for a Sanfilippo child, and they have difficulty adjusting to a new routine.
Sanfilippo children develop slowly both mentally and physically, then not at all. By the age of 10, a Sanfilippo child usually cannot walk (there are exceptions). They lose both strength and coordination during that time. Physical therapy can and does help, but it does not stop progression of the disease.
As the damage progresses, the Sanfilippo child eventually loses the ability to eat or swallow. They withdraw from the world, and some eventually do not recognize even their loved ones. Blindness or greatly diminished vision is common.
A person with Sanfilippo Syndrome will ultimately succumb to the cumulative effects of the disease. There is a lot of variability in when that happens, and in the speed of the progression of the disease. Some children succumb to the effects of the disease before or during their teens. Others grow into their twenties before the accumulated effects lead to a fatal event (often respiratory failure). There are instances of persons with Sanfilippo syndrome who are in their 30′s. It is uncommon, however.
How do other MPS diseases compare to Sanfilippo syndrome?
All of the six different types of MPS diseases (MPS I through MPS VI) are the result of an enzyme deficiency that creates a buildup of GAGs. The enzymes are different in the various MPS diseases. Because of this, the end waste products differ, and the most affected organs differ as well. As a result, the symptoms and expected outcomes of the MPS diseases are somewhat different, although there are considerable similarities, too. [Mucopolysaccharidoses are inherited metabolic disorders in which glycosaminoglycans (GAGs) accumulate within lysosomes of cells producing progressive organ system damage.]The current state of treatment options for Sanfilippo syndrome
ERT administered intravenously does not relieve the problems that may exist in the central nervous system, because it does not cross the blood brain barrier (a membrane that serves as a gatekeeper to prevent foreign substances from entering the brain and/or spinal cord). However for some MPS diseases, functions of other organs and mobility can be improved.
A specific artificial enzyme for MPS III Type A has been developed by Shire Human Genetic Therapies. Shire HGT also developed the Elaprase artifial enzyme that is now in commercial use for Hunter syndrome patients via infusion.
The blood-brain barrier is the reason why ERT via infusion has not been used for Sanfilippo syndrome patients. The inability of the enzyme to cross the BBB makes the standard IV infusion technique of small value for MPS III patients. The blood-brain barrier also limits the benefits of the standard infusion technique into the bloodstream for Hunter syndrome patients, although not to the same degree as it would for MPS III patients.
Shire Human Genetic Therapies (Shire HGT) is developing a sulfamidase enzyme replacement therapy (ERT)rhHNS for patients with MPS IIIA. rhHNS is being administered into the cerebrospinal fluid (CSF) via a surgically implanted intrathecal drug delivery device (IDDD). When administered intravenously (IV), the enzyme does not cross the blood brain barrier (BBB).
This study is a multicenter, multiple-dose, dose escalation study designed to evaluate the safety, tolerability, and clinical activity of up to 3 dose levels (2 doses [10 and 45mg] monthly and 1 dose [45mg] every other week for 6 months) of rhHNS administered via an IDDD in patients with Sanfilippo syndrome Type A ages greater than or equal to 3 years of age.
The phase I/II clinical trial will enroll up to 15 patients, and began in June, 2010. The study is expected to be completed March 2012. The duration of the study for each patient is nine months.
Patients who have completed all study requirements in this study will be invited to participate in an open-label extension study that will be designed to evaluate long term safety and clinical outcomes of intrathecal administration of rhHNS.
The Phase I / II clinical study is being conducted at two sites: Emma Children’s Hospital, Academic Medical Center in The Netherlands by Dr. Frits Wijberg and the St. Mary’s Hospital in Manchester, UK under the direction of Drs. Simon Jones and Ed Wraith. Enrolled children are residents of the two countries in which the trials are being conducted.