Mucopolysaccharidosis Type III (Sanfilippo Syndrome)
Mucopolysaccharidosis type III, also known as Sanfilippo syndrome, is a rare inherited disease that primarily affects the brain and spinal cord, causing progressive damage to the nervous system in early childhood.
Table of contents
- What is Mucopolysaccharidosis Type III?
- Other Names for This Condition
- Different Types of MPS III
- What Causes This Disease?
- How Common is MPS III?
- Signs and Symptoms
- How is MPS III Diagnosed?
- Treatment and Management
- Life Expectancy and Outlook
- How is MPS III Inherited?
- Support and Resources
What is Mucopolysaccharidosis Type III?
Mucopolysaccharidosis type III (MPS III) is a rare disease in which the body is missing or does not have enough of certain enzymes (special proteins that help break down substances in the body) needed to break down long chains of sugar molecules called glycosaminoglycans (formerly called mucopolysaccharides).[1] As a result, these molecules build up in different parts of the body and cause various health problems.[4]
The condition primarily affects the brain and spinal cord, which together make up the central nervous system.[1] It is characterized by deterioration of brain function, resulting in many of the features of the condition. While other body systems can also be involved, the physical features are usually mild in the early stages.[1]
People with MPS III generally do not display any features of the condition at birth, but they begin to show signs and symptoms during early childhood.[1] The disease causes progressive intellectual disability and the loss of previously acquired skills.[1]
Sanfilippo syndrome, MPS III
Other Names for This Condition
This disease is also known as Sanfilippo syndrome. It takes its name from Dr. Sylvester Sanfilippo, one of the U.S. doctors who described the condition in 1963.[6]
Different Types of MPS III
MPS III is divided into four main types: A, B, C, and D. These types are distinguished by which specific enzyme is missing or not working properly.[1] The different types have similar signs and symptoms, although the features of MPS IIIA typically appear earlier in life and progress more rapidly.[1]
Type A is caused by a defect in the SGSH gene and is the most severe form. People with this type do not have a normal form of the enzyme called heparan N-sulfatase.[4] Type A is the most common subtype globally.[13]
Type B is caused by a defect in the NAGLU gene. People with this type are missing or do not produce enough alpha-N-acetylglucosaminidase.[4] Some mild cases of the B form have seen affected individuals stay relatively healthy into adult life.[6]
Type C is caused by a defect in the HGSNAT gene. People with this type are missing or do not produce enough acetyl-CoA:alpha-glucosaminide N-acetyltransferase.[4]
Type D is caused by a defect in the GNS gene. People with this type are missing or do not produce enough N-acetylglucosamine 6-sulfatase.[4] Type D is the least common subtype.[5]
What Causes This Disease?
Changes in genes (also called variants or mutations) in the GNS, HGSNAT, NAGLU, and SGSH genes cause MPS III. These genes provide instructions for making enzymes involved in the breakdown of large sugar molecules called glycosaminoglycans.[1] Glycosaminoglycans were originally called mucopolysaccharides, which is where this condition gets its name.[1]
The enzymes affected in MPS III are involved in the step-by-step breakdown of a specific type of glycosaminoglycan called heparan sulfate.[1] Variants in these genes reduce or eliminate enzyme function. A lack of any one of these enzymes disrupts the breakdown of heparan sulfate.[1]
As a result, partially broken down heparan sulfate accumulates within cells, specifically inside compartments called lysosomes (small sacs within cells that break down and recycle different types of molecules).[1] These materials remain stored in the body’s cells, causing progressive damage. Babies may show little sign of the disease, but as cells sustain damage, symptoms start to appear.[6]
How Common is MPS III?
MPS III is the most common form of mucopolysaccharidosis. The estimated incidence of all four types combined is 1 in 70,000 newborns.[1] Researchers also estimate that it affects 1 person per every 50,000 to 250,000 people.[5]
MPS IIIA and MPS IIIB are much more common than MPS IIIC and MPS IIID.[1] Sanfilippo syndrome type A is the most common subtype globally, while Type D is the least common.[5]
Signs and Symptoms
The age of onset, severity, and progression of the disease can vary greatly between patients with different subtypes and within the same subtype.[3] Development during pregnancy and early life after birth progresses normally.[3]
Early Childhood Symptoms
Symptoms often appear after the first year of life. Between the ages of one and four is when the disease typically shows itself.[3] Affected infants appear normal, although some mild facial differences may be noticeable.[3]
Early signs and symptoms can include frequent ear and throat infections or bowel problems, though most common are mild developmental delay or delayed speech.[1] A decline in learning ability typically occurs between ages 2 and 6.[4] The child may have normal growth during the first few years, but final height is below average.[4]
Behavioral and Neurological Changes
Behavioral problems often worsen with affected children becoming restless, hyperactive, destructive, anxious, impulsive, fearless, or aggressive.[1] Between the ages of three and ten, the disease progresses to increasing behavioral disturbance including temper tantrums, hyperactivity, destructive behavior, aggressive behavior, difficulties with toilet training, and sleep disturbance.[3]
Some affected children display features of autism spectrum disorder, which is a condition characterized by difficulty with social interactions and communication.[1] Children with MPS III may have an increased tendency to chew on objects or put things in their mouth. Sleep disturbances are also very common.[1]
This condition causes progressive intellectual disability and the loss of previously acquired skills (called developmental regression or dementia).[1] In later stages of the disorder, people with MPS III may develop seizures, loss of mobility, and movement disorders.[1]
Physical Features
The physical features of MPS III are less pronounced than those of other types of mucopolysaccharidosis.[1] Of all of the MPS diseases, Sanfilippo syndrome produces the fewest physical abnormalities.[3]
Individuals with MPS III typically have mildly “coarse” facial features, including broad eyebrows that may meet in the middle of the face, a prominent forehead, a large head, and thick hair and eyebrows.[1] Some people with MPS III have short stature, joint stiffness, or multiple skeletal abnormalities seen on x-ray.[1]
Other symptoms may include chronic diarrhea, an enlarged liver and spleen, a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia).[1] Walking problems and stiff joints that may not extend fully can also occur.[4]
Heart, Vision, and Hearing Problems
Cardiac abnormalities may occur, including weakening of the heart muscle (cardiomyopathy), disruption of the heart’s normal rhythm (arrhythmia), or problems with the heart’s valves.[1] Affected individuals often experience recurrent upper respiratory and ear infections.[1] People with MPS III may also have hearing loss and vision problems.[1]
How is MPS III Diagnosed?
Your health care provider will perform a physical exam.[4] The diagnosis of MPS III is established when suggestive clinical and laboratory findings are present and either changes in one of the four genes (GNS, HGSNAT, NAGLU, and SGSH) or deficiency of the respective enzyme has been identified.[2]
Urine tests will be done. People with MPS III have a large amount of a mucopolysaccharide called heparan sulfate in the urine.[4]
Other tests may include blood enzyme level testing, an echocardiogram (ultrasound of the heart), genetic testing, a slit lamp eye exam, skin fibroblast culture (testing of skin cells), and x-rays of the bones.[4]
Treatment and Management
Treatment of MPS III is aimed at managing the symptoms. There is no specific treatment for this disease that can cure it.[4] Medical treatment is supportive and is directed toward improving the patient’s quality of life.[9]
Current Management Approaches
Because of the varied symptoms seen in MPS III, a multidisciplinary approach is indicated.[9] Treatment of manifestations includes supportive therapies for developmental delays, hearing loss, and visual impairment; medications (rather than behavioral therapy) for psychiatric and behavioral issues; physical therapy and/or orthopedic management of skeletal problems; and management as prescribed by consulting specialists for seizures, cardiac involvement, sleep disorders, and feeding difficulties.[2]
Why Standard Therapies Don’t Work
Specific therapies such as bone marrow transplantation and standard enzyme replacement therapy are not options for patients with Sanfilippo syndrome.[9] Bone marrow transplants have been tried on individuals with MPS III, but with disappointing results.[6] Recombinant enzymes for the deficiencies are available; however, medical trials in enzyme replacement therapy have not been favorable because the enzymes are not able to cross the blood-brain barrier to enter the central nervous system.[9]
Treatments Under Investigation
New research is under development for gene therapy and enzyme replacement.[4] Gene therapy, chaperone therapy, and intrathecal enzyme therapy (enzyme delivered directly into the fluid around the brain and spinal cord) are a few of the treatments for MPS III where research is ongoing.[6] Despite ongoing research for a variety of therapeutic options, no treatments are currently clinically available for treatment of the primary manifestations of MPS III.[2]
Regular Monitoring
Routine monitoring is important and includes tracking developmental capabilities and educational needs, destructive or disruptive behaviors, skeletal involvement, hearing, and cardiac involvement.[2]
Life Expectancy and Outlook
MPS III causes significant nervous system symptoms, including severe intellectual disability.[4] People with MPS III usually live into adolescence or early to mid-adulthood.[1] Most people with MPS III live into their teenage years.[4]
Death usually occurs in the second or third decade of life secondary to brain damage or respiratory tract infections.[2] Some live longer, while others with severe forms die at an earlier age.[4] Symptoms are most severe in people with type A.[4]
The disease affects each person differently, and its progress will be much faster in some individuals than in others.[6] Some individuals with an extremely slow disease course present in mid-to-late adulthood with early-onset dementia with or without a history of intellectual disability.[2]
Possible Complications
These complications can occur: blindness, inability to care for self, intellectual disability, nerve damage that slowly gets worse and eventually requires wheelchair use, and seizures.[4]
How is MPS III Inherited?
MPS III is an inherited disorder, which means it is typically passed down through families.[4] It is inherited in an autosomal recessive manner. This means that if both parents carry a nonworking copy of a gene related to this condition, each of their children has a 25% (1 in 4) chance of developing the disease.[4]
MPS III is caused by a recessive gene. At conception, each sibling of an affected individual has a 25% chance of being affected.[2] There is a two in three chance that unaffected brothers and sisters of MPS III patients will be carriers.[6]
Genetic counseling is recommended for couples who want to have children and who have a family history of MPS III.[4] Biological parents and their families should be offered genetic counseling to discuss the recurrence risk after the birth of an affected child.[9] Prenatal testing is available.[4]
Support and Resources
More information and support for people with MPS III and their families can be found at several organizations. The National MPS Society provides resources and support for families affected by mucopolysaccharidosis disorders.[4] The National Organization for Rare Disorders and the NIH Genetic and Rare Diseases Information Center also offer information about MPS III.[4] The Team Sanfilippo Foundation is another resource specifically focused on this condition.[4]
Contact your child’s provider if your child does not seem to be growing or developing normally. See your provider if you plan to have children and you have a family history of MPS III.[4]
