Sanfilippo syndrome
Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a progressive genetic disorder that primarily impacts the central nervous system due to a deficiency in enzymes necessary for breaking down heparan sulfate. This condition arises from mutations in one of four specific genes, leading to an accumulation of heparan sulfate and other substances in the body, particularly in the brain. There are four recognized subtypes of Sanfilippo syndrome—A, B, C, and D—each associated with mutations in different genes.
The syndrome typically presents in three phases, starting with developmental delays noticeable by age two, followed by behavioral issues and hyperactivity, and culminating in significant motor skill loss and feeding difficulties. Currently, there is no cure for Sanfilippo syndrome, and treatment options are primarily experimental, focusing on potential enzyme replacement, substrate deprivation therapy, and gene therapy. Genetic testing allows for early diagnosis, and families with a history of the condition face a 25% risk of having another affected child. Despite ongoing research efforts, individuals with Sanfilippo syndrome generally have a reduced life expectancy, often not living beyond their late twenties or early thirties.
Sanfilippo syndrome
ALSO KNOWN AS: Mucopolysaccharidosis type III; MPS III
DEFINITION: Sanfilippo syndrome is a progressive disorder that primarily affects the central nervous system. In individuals with Sanfilippo syndrome, gene mutations cause a deficiency of an enzyme needed for the breakdown of heparan sulfate. There are four subtypes of Sanfilippo syndrome: A, B, C, and D.
Risk Factors
A family history of Sanfilippo syndrome is the most significant risk factor. The parents of a child with Sanfilippo syndrome have a 25 percent chance to have another child with the condition. Unaffected siblings of an individual with Sanfilippo syndrome have a 67 percent chance to be carriers of the condition. There is a high incidence of Sanfilippo syndrome in individuals from the Cayman Islands.
Etiology and Genetics
Sanfilippo syndrome is an autosomal recessive condition. Humans typically have twenty-three pairs of chromosomes. The first twenty-two pairs are the autosomes and are numbered 1 through 22. The twenty-third pair consists of the sex chromosomes, which are called X and Y. Each chromosome contains many genes. Humans have two copies of most genes. Individuals affected with an autosomal recessive condition have a mutation in both copies of a given gene. In autosomal recessive conditions, individuals with a mutation in one copy of a gene are considered carriers. Mutations in one of four genes (SGSH, NAGLU, HGSNAT, GNS) cause each type of Sanfilippo syndrome (A, B, C, D, respectively). SGSH and NAGLU are both located on chromosome 17. HGSNAT is located on chromosome 8, and the GNS gene is located on chromosome 12.
Each of the four genes for Sanfilippo syndrome provides instructions for a single enzyme, which is partially responsible for the breakdown of heparan sulfate. Heparan sulfate is a type of mucopolysaccharide, which are complex chains of sugar molecules. Because heparan sulfate is broken down in the lysosome of the cell, Sanfilippo syndrome is considered a lysosomal storage disease.
Individuals with Sanfilippo syndrome have heparan sulfate stored in the body’s tissues. However, the majority of heparan sulfate is stored in the brain. It is also believed that the storage of heparan sulfate interferes with the breakdown of a component of cell membranes, gangliosides. The combination of heparan sulfate and ganglioside accumulation causes the symptoms of Sanfilippo syndrome.
Symptoms
Types A, B, C, and D of Sanfilippo syndrome have similar symptoms, and the type cannot be determined based on symptoms. Sanfilippo syndrome is a progressive disorder that primarily affects the central nervous system. As the condition progresses, the neurological symptoms gradually change. The symptoms of Sanfilippo syndrome are divided into three phases. The timing and severity of each phase vary from one individual to the next. Phase one is characterized by developmental delay, which is typically identified between twelve months and twenty-four months of age. The delay is typically most significant in speech. The second phase is usually from age three to age ten and is characterized by hyperactivity and behavioral problems. A need for very little sleep may develop during phase two. The third phase typically begins at the end of the first decade. Individuals slowly lose motor skills and eventually are no longer able to walk. Swallowing problems may also develop during the third phase.
Screening and Diagnosis
Mucopolysaccharides are also known as glycosaminoglycans (GAGs). Quantification of GAGs in urine is a screening test for all mucopolysaccharidoses. Thin-layer chromotography (TLC) separation is another screening test that may identify a specific mucopolysaccharidosis. However, if quantification of GAGs and TLC separation is abnormal, then confirmatory enzyme analysis is necessary.
Treatment and Therapy
Unfortunately, there is currently no therapy or treatment for Sanfilippo syndrome. However, several potential treatments are currently being researched. Replacing the missing enzyme is a potential treatment; however, the enzyme is unable to get through the protective coating around the brain. Because the symptoms of Sanfilippo syndrome are primarily neurological, the enzyme must be administered directly into the brain. Substrate deprivation therapy (SDT) is a pharmaceutical approach to reduce the amount of GAGS or gangliosides produced by the body. Two SDTs, miglustat and genistein, have been trialed in patients with Sanfilippo syndrome, with some stabilization of neurological symptoms. In 2024, researchers published the results of a clinical trial that demonstrated the potential effectiveness of the anti-inflammatory drug anakinra in treating Sanfilippo syndrome. The trial demonstrated that treatment with anakinra successfully reduced harmful inflammation in the brains and bodies of patients with Sanfilippo syndrome and lessened symptoms of the disease. Gene therapy is another potential treatment and is currently being researched in animal models. Some of these experimental measures have shown some promise, but a cure remains far off.
Prevention and Outcomes
Genetic testing is available for all four types of Sanfilippo syndrome. If gene mutations are identified in an individual with Sanfilippo syndrome, then preimplantation genetic diagnosis, chorionic villus sampling, and amniocentesis are available to the parents for prevention. Individuals with Sanfilippo syndrome do not typically survive past their late twenties or early thirties.
Bibliography
Fernandes, John, Jean-Marie Saudubray, Georges van den Berghe, and John H. Walter. Inborn Metabolic Diseases. 4th ed. Germany: Springer, 2006. Print.
Heldermon, C. D., et al. “Disease Correction by Combined Neonatal Intracranial AAV and Systemic Lentiviral Gene Therapy in Sanfilippo Syndrome Type B Mice.” Gene Therapy 20.9 (2013): 913–21. Print.
Jakobkiewicz-Banecka, Joanna, Alicja Wegrzyn, and Grzegorz Wegrzyn. “Substrate Deprivation Therapy: A New Hope for Patients Suffering from Neuronopathic Forms of Inherited Lysosomal Storage Diseases.” Journal of Applied Genetics 48.4 (2007): 383–88. Print.
Mehta, Atul B., and Bryan Winchester. Lysosomal Storage Disorders: A Practical Guide. Chichester: Wiley, 2013. Print.
Milunsky, Aubrey, and Jeff M. Milunsky. Genetic Disorders and the Fetus: Diagnosis, Prevention, and Treatment. 6th ed. Chichester: Wiley, 2010. Print.
Nussbaum, Robert L., Roderick R. McInnes, and Huntington F. Willard. Thompson and Thompson Genetics in Medicine. 7th ed. New York: Saunders, 2007. Print.
Pearse, Yewande, and Michelina Iacovino. "A Cure for Sanfilippo Syndrome? A Summary of Current Therapeutic Approaches and their Promise." Medical Research Archives, vol. 8, no. 2, 21 Feb. 2020, doi: 10.18103/mra.v8i2.2045. Accessed 3 Sept. 2024.
Polgreen, Lynda E., et al. "Anakinra in Sanfilippo Syndrome: A Phase 1/2 Trial." Nature Medicine, 21 June 2024, doi.org/10.1038/s41591-024-03079-3. Accessed 3 Sept. 2024.
Valstar, M. J., et al. “Sanfilippo Syndrome: A Mini Review.” Journal of Inherited Metabolic Disease 31 (2008): 240–52. Print.