Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a rare lifelong genetic disease that mainly affects the brain and spinal cord. It is caused by a problem with how the body breaks down certain large sugar molecules called glycosaminoglycans (also known as GAGs or mucopolysaccharides). In children with this condition, these sugar molecules build up in the body and eventually lead to damage of the central nervous system and other organ systems.

Children with Sanfilippo syndrome do not usually show any problems at birth. As they grow, they may begin having trouble learning new things and might lose previously learned skills. As the disease progresses, they may develop seizures and movement disorders. Most children with Sanfilippo syndrome live into adolescence or early adulthood.

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. Development during the prenatal and early post-natal stages progresses normally. Between the ages of one and four is when the disease typically manifests. Affected infants appear normal, although some mild facial dysmorphism may be noticeable. Of all of the MPS diseases, Sanfilippo syndrome produces the fewest physical abnormalities. Possible clinical somatic symptoms, although rare, include coarse facial features with broad eyebrows, dark eyelashes, dry and rough hair, and skeletal pathology that affects growth. Children usually present with delayed cognitive development and behavioral problems, followed by progressive intellectual decline resulting in severe dementia and progressive motor disease. Acquisition of speech is often slow and incomplete. Although delayed cognitive development may occur, it tends to be mild in individuals with Sanfilippo syndrome.

Between the ages of three and ten, the disease progresses to increasing behavioral disturbance including temper tantrums, hyperactivity, destructive behavior, aggressive behavior, pica, difficulties with toilet training, and sleep disturbance. People with this disorder may stay in this phase for five to ten years. Persons with Sanfilippo syndrome tend to regress to an unresponsive or vegetative state until they pass away. Other signs less frequently seen in persons with Sanfilippo syndrome include behavioral changes and musculoskeletal changes such as increased muscle and joint stiffness and changes in bone growth or density. By the age of 4, mostly male children with Sanfilippo syndrome were still taller than unaffected children. Type A is usually the most severe subtype, characterized by the earliest onset, rapid clinical progression with severe symptoms, and short survival, with patients' life expectancy averaging between 15 and 18 years old.

{| class="wikitable"

|+ Genetics of MPS-III

! Sanfilippo syndrome type !! Gene !! Enzyme !! Chromosomal region || Number of known mutations causing this type

|-

! Type A

| SGSH || heparan N-sulfatase

|-

! Type B

| NAGLU || Alpha-N-acetylglucosaminidase These chains of sugar molecules, known as glycosaminoglycans or GAGs, are found in different parts of cells and tissues, such as the extracellular matrix and the cell membrane, or stored in the secretory granules (which are small particles inside cells). Normally, special enzymes found in lysosomes, the cell's recycling centers, break down these sugar chains. These degrading enzymes include glycosidases, sulfatases, and acetyltransferases and a deficiency or absence in any one of these enzymes can lead to improper breakdown of heparan sulfate. The sugar chains accumulate in the cell's lysosomes eventually causing cell damage, dysfunction, and death; how it works is not fully understood. The build up of these sugar molecules can occur in the brain, spinal cord, and connective tissue of various organ systems which are what led to the range of symptoms associated with Sanfilippo syndrome.

Sanfilippo syndrome is associated with a wide range of symptoms due to the protein heparan sulfate is attached to, heparan sulfate proteoglycans (HSPGs). HSPGs are key players in various signaling pathways and controls neural progenitor proliferation and other essential processes within the central nervous system (CNS). Additionally, urinary GAG levels are higher in infants and toddlers than in older children. In order to avoid a false negative urine test due to dilution, it is important that a urine sample be taken first thing in the morning. The diagnosis may be confirmed by enzyme assay of skin fibroblasts and white blood cells, as well as gene sequencing. Through gene sequencing, known genetic defects can be detected in order to identify the disease. Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Diagnosing individuals with Sanfilippo syndrome can be challenging because of the rarity of the disease and variability of the presentation in early symptoms and an accurate diagnosis may take years. Due to the neurological symptoms presented in Sanfilippo syndrome, misdiagnoses can occur, such as developmental delays, attention deficit/hyperactivity disorder (ADHD), or autism spectrum disorder (ASD) diagnoses being made. Moreover, other medical conditions that present with physical symptoms such as juvenile idiopathic arthritis or behavioral issues such as Landau–Kleffner syndrome can be mistaken for the disease and prevent early diagnosis of Sanfilippo. Additionally, screening for Sanfilippo syndrome is not a routine procedure, which can also delay a proper diagnosis to have the best possible management.

Supportive therapies to manage Sanfilippo syndrome include the use of medications, physical therapy, medical equipment, surgery, and occupational therapy to treat behavioral and cognitive delays, musculoskeletal damage, and to improve overall quality of life. Patients that underwent bone marrow transplant before the age of two showed neurocognitive function stabilization. Although the missing enzyme can be manufactured and given intravenously (also known as enzyme replacement therapy) to help treat other non-neurological lysosomal storage diseases and Sanfilippo syndrome with minor neurological impacts, it cannot penetrate the blood–brain barrier and therefore cannot treat the moderate to severe neurological manifestations of MPS-III.

Gene therapy in particular is under Phase I/II clinical trial in France since October 2011 under the leadership of Paris-based biotechnology company Lysogene. Other potential therapies include chemical modification of deficient enzymes to allow them to penetrate the blood–brain barrier, stabilization of abnormal but active enzyme to prevent its degradation, and implantation of stem cells strongly expressing the missing enzyme. For any future treatment to be successful, it must be administered as early as possible. Currently, MPS-III is mainly diagnosed clinically, by which stage it is probably too late for any treatment to be very effective. Neonatal screening programs would provide the earliest possible diagnosis.

Another treatment currently being studied is enzyme replacement therapy, which works by replacing the enzyme that is not present or deficient by infusing the enzyme into the body. However, a challenge of this treatment option is that the enzymes being replaced do not have the ability to cross the blood–brain barrier, one of the places sulfate heparan accumulates.

Several support and research groups have been established to speed the development of new treatments for Sanfilippo syndrome.

Prognosis

According to a study of people with Sanfilippo syndrome, the median life expectancy varies depending on the subtype. In Sanfilippo syndrome type A, the mean age at death (± standard deviation) was 15.22 ± 4.22 years; for type B, it was 18.91 ± 7.33 years; and, for type C, it was 23.43 ± 9.47 years. The mean life expectancy for type A has increased since the 1970s. In severe cases of Sanfilippo syndrome, less than twenty percent of people survive past 20 years of age. The point prevalence (the proportion of people in a population that has the trait at a given point of time) can vary from 1 to 9 in 1,000,000 people. 1 per 66,000 in Australia, and 1 per 50,000 in the Netherlands. Globally, there are an estimated 12,000 to 19,000 individuals living with types A, B, and C. Subtypes A and B are predominately found in Europe, with subtype A specific to the northern region and subtype B specific to the southern region.

Society and culture

The economic burden of Sanfilippo syndrome worldwide has not been studied; however, new research shows the disease's impact in monetary and disability-adjusted life year (DALYs) terms in the United States. DALYs stands for "disability-adjusted life years" and the article describes it as "...years of life lost from early death and the years lived with a disability or ill-health, compared to a typical healthy life." The disease is estimated to cost the U.S. $1.55 billion in the next twenty years, and due to the heavy burden caregivers of children with Sanfilippo syndrome carry, they were estimated to lose an average of 2.08 DALYs (father) or 4.08 DALYs (mother), with an economical loss of $4.54 million and $5.61 million DALYs. A child diagnosed with the disease loses 53 (male) or 58 DALYs (female). however, quantitative data revealed that parents of children with Sanfilippo syndrome have reported they would like to see therapies that target both behavioral issues such as lack of communication, hyperactivity, and frustration, as well as physical symptoms such as motor and sleep issues. They believe these types of treatments would greatly reduce the burden for both parties. Parents also specified their willingness to try experimental treatments, but were disappointed that most clinical trials limited access to younger children with less disease progression.

A best-practice guidance to help clinicians understand the challenges caregivers face was published July 2019 in the Orphanet Journal of Rare Diseases by a group of international clinical advisors with expertise in the care of pediatric patients with Sanfilippo, lysosomal storage disorders, and life as a caregiver to a child with Sanfilippo.