Sanfilippo syndrome, or mucopolysaccharidosis type III (MPS III), is a rare neurodegenerative disease that first appears in early childhood.

There are four subtypes of Sanfilippo syndrome: A, B, C, and D. Each subtype is the result of a specific enzyme deficiency. The subtype determines both the severity and prevalence of the condition. The symptoms vary among individuals but typically worsen as the child gets older.

This article discusses the cause, symptoms, diagnosis, and treatment of Sanfilippo syndrome. It also looks at the outlook for people with this condition.

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Sanfilippo syndrome is a progressive disease that primarily affects the central nervous system. Approximately 1 in 70,000 children are born with the condition, but the symptoms do not typically appear until the third year of life or beyond.

Type A is the most common and most severe subtype of the condition. The next most common subtype is type B, though some countries in Southern Europe report more cases of type B than type A. Meanwhile, types C and D are the rarest, representing roughly 1 in 1.5 million and 1 in 1 million cases, respectively.

All four subtypes of Sanfilippo syndrome relate to central nervous system deterioration. Individuals with this condition are missing, or have a dysfunctional version of, a key enzyme necessary to break down long chains of sugar molecules called mucopolysaccharides, or glycosaminoglycans (GAGs). Without this enzyme, the molecules build up in the body. This accumulation can lead to severe brain damage and regression in development.

People with Sanfilippo syndrome have a high mortality rate that varies depending on the subtype. A 2017 study indicates that the mean age at death for those with MPS III type A is 11–19 years. Those with type B or C have a longer life expectancy that typically ranges from about 11 to 34 years. The study did not include type D, but people with this variation will also likely live into adolescence or early adulthood.

On average, an individual with Sanfilippo syndrome has a life expectancy of 2–3 decades. That said, the longevity of those with type A appears to have improved significantly in the past several decades. There is insufficient research on the other subtypes to determine any notable changes.

All four subtypes of Sanfilippo syndrome are the result of a genetic variation, mutation, or deficiency that prevents the body from breaking down heparan sulfate. Heparan sulfate is a complex sugar molecule that is part of the GAG family. The body creates long chains of GAGs and breaks them down through metabolic processes to aid in:

  • cell growth
  • cell signaling
  • wound repair
  • connective tissue growth
  • cartilage repair and growth
  • nerve tissue building
  • blood clotting

When the body does not have the required enzyme, heparan sulfate accumulates rather than breaking down. This buildup can then lead to the following:

  • neurodevelopmental delay
  • neurological deterioration
  • organ damage
  • growth problems
  • behavioral changes

Each of the four subtypes of Sanfilippo syndrome is due to a deficiency or mutation in one of the four main enzymes that the body needs to break down heparan sulfate. In brief, each subtype of the condition features a characteristic deficiency or lack of the following:

  • SGSH gene, in MPS IIIA
  • NAGLU gene, in MPS IIIB
  • HGSNAT gene, in MPS IIIC
  • GNS gene, in MPS IIID

Genetics plays an important role in Sanfilippo syndrome, which is an autosomal recessive disorder. This term means that the child of two people who are carriers for Sanfilippo syndrome will have a 25% chance of developing the condition.

Although children are born with Sanfilippo syndrome, the symptoms rarely appear until the child is 2–6 years old. Early symptoms of the condition may include:

  • delays in development or speech
  • behavioral issues, such as hyperactivity or compulsive disorders
  • difficulty sleeping
  • chronic diarrhea
  • stiff joints
  • mobility issues that may cause difficulty walking
  • larger-than-normal head size or distinctive facial features, such as heavy eyebrows

The symptoms may worsen as the child gets older, although the rate of progression varies. There are three main stages of developmental issues in individuals with Sanfilippo syndrome. These are as follows:

  • Stage 1: From 1–4 years of age, the child may display mild delays in cognitive development. They may also have frequent ear, nose, or throat infections or diarrhea.
  • Stage 2: Between the ages of 3 and 5 years, the child may exhibit behavioral issues, have trouble sleeping, or experience a decline in cognitive development. This stage lasts up to 10 years.
  • Stage 3: Finally, the child may start to regress when it comes to cognitive function and basic motor skills. In most cases, children lose their language skills before they lose the ability to walk or feed themselves. In stage 3, the child also experiences other physical problems, such as difficulty breathing or seizures.

The early diagnosis of Sanfilippo syndrome is crucial in ensuring that a child gets the support they need. In addition to a standard physical exam, there are several effective ways to diagnose the condition, including:

Urine MPS analysis is a test specifically designed to identify the quantity of GAGs and certain molecules, such as heparan sulfate, keratan sulfate, and dermatan sulfate, in the body.

If the urine test results are positive, a doctor may perform a blood enzyme test to confirm the findings. This test can determine whether one of the enzymes that the body uses to break down heparan sulfate is missing. It is also a recommended test for younger people or those who cannot provide a usable urine sample.

Another option is genetic testing, which requires a blood or saliva sample. Genetic testing checks for congenital anomalies and known mutations in genes associated with Sanfilippo syndrome.

Some parents or caregivers may opt for supplemental screening for newborns under 1 year of age. Although not an official part of the newborn screening public health program, this screening may help identify MPS IIIA.

There is currently no cure for Sanfilippo syndrome. However, researchers have conducted stem cell research and clinical trials using animal and cellular models. These clinical trials have investigated:

  • enzyme replacement therapy (ERT)
  • gene therapy
  • substrate reduction therapy (SRT)

Gene therapy and ERT are currently the most promising treatment options for the condition. For example, weekly intravenous ERT may help stabilize the condition. Although more research in human trials is still necessary, many of these treatments do help with other forms of MPS and neurodegenerative diseases. They may also help ease some of the symptoms of MPS III and improve the individual’s quality of life.

Sanfilippo syndrome is a debilitating condition that typically results in a shorter life expectancy. On average, an individual with Sanfilippo syndrome has a life expectancy of 2–3 decades.

With the help of ongoing research, more clinical trials, and financial assistance from the government or pharmaceutical companies, it may be possible to develop a more effective treatment for people with the condition. In the meantime, early treatment may help manage some of the worst symptoms and improve the individual’s quality of life.

Sanfilippo syndrome, or MPS III, is a fatal condition that affects an individual’s nervous system and neurological development. It is the result of a mutation leading to a deficiency of one of the enzymes necessary to break down heparan sulfate. Individuals with a family history of Sanfilippo syndrome have a greater likelihood of developing the condition.

There are several types of Sanfilippo syndrome, but the most common types are MPS IIIA and MPS IIIB. The early symptoms are often mild, but severe symptoms begin to show up as the child gets older. These symptoms include behavioral disorders, developmental issues, and a loss of mobility.

Several treatment options are available to those with Sanfilippo syndrome, ranging from enzyme replacement therapy to gene therapy. These treatments may help manage or ease symptoms to improve the individual’s quality of life. Although there have been some clinical trials, there is currently no cure for the condition.