Aging in Reverse: The Devastating Consequences of Sanfilippo Syndrome

What is Sanfilippo Syndrome? 

Everyone is familiar with Alzheimer’s and dementia. Many have a loved one who suffers from the disease. It is unlikely though that you have met a child who suffers from the same symptoms that progress even faster. Sanfilippo syndrome is deemed a rare disease with less than 5,000 current cases in the United States [1]. As opposed to adults who can live for years without symptoms of Alzheimer’s, Sanfilippo creeps in on vulnerable children and snatches their innocence only to realize it once it is too late. Sanfilippo syndrome is an extremely rare, genetic, metabolic disorder that mimics the brain damage found in patients with dementia or Alzheimer’s disease but in children; this article will examine the genetic causes, symptoms, and new, cutting-edge treatments.

Signs and Symptoms

Beginning from the age of two to six, children with Sanfilippo syndrome are challenged with developmental delays restricting their speech and motor functions due to the degradation of the central nervous system (CNS) which consists of the brain and spinal cord. Many children also present with restless and anxious behavior; their hyperactivity is so severe that they can go days without sleep. Other physical symptoms like macrocephaly (enlarged head), short forehead, excess hair growth, and full, bushy eyebrows serve as hallmark characteristics for children with Sanfilippo syndrome [2]. It can be difficult to pinpoint the source of these symptoms as many overlap with more common disorders. Children with Sanfilippo are often misdiagnosed with Autism Spectrum Disorder (ASD) or Attention Deficit/Hyperactivity Disorder (ADHD). The overlapping symptoms include repetitive habits, anxious and hyperactive behaviors, restrictive and special interests, and difficulty speaking. Like Alzheimer’s disease in adults, Sanfilippo strips children of all ability to take care of themselves and engage in age-appropriate activities. When the disease progresses, families must uproot their normal dynamics to care for their child around clock [3].

Pathology and Pathophysiology

Recessive Nature

Sanfilippo syndrome is a recessive genetic disorder; the child receives a copy of the mutated gene from both parents. This gene is responsible for encoding a specific enzyme that breaks down complex sugars in the CNS. The mutation results in an enzyme deficiency and sugar surplus which then leads to CNS deterioration over time. Scientists have not been able to understand the mechanism of how the sugar surplus lends itself to CNS injury [2].

Lysosomal Storage Disorders

The clinical name for Sanfilippo syndrome is mucopolysaccharidosis type III (MPS III) and it belongs to a larger sector of pathologies known as lysosomal storage disorders (LSDs) [2]. Enzymes are proteins that help speed up chemical reactions, allowing cells to function and break down sugars in this case. Lysosomes serve as the digestive system of the cell by breaking down molecules like carbohydrates and sugars. A lysosome cannot carry out its duties, however, without its trusty sidekick, the enzyme. LSDs are characterized by the lysosomes’ inability to break down matter efficiently, or at all. The buildup of excess materials inside the cells inhibits the proper functioning of biological systems like the nervous, endocrine, and immune systems [4]. Specifically, Sanfilippo syndrome inhibits the enzyme responsible for breaking down heparan-sulfate, a complex sugar, and results in irregularities in the CNS. The degradation mechanism is not fully understood by scientists, but the accumulation of heparan-sulfate prevents proper regulation of cell development, cell-to-cell interaction, and metabolism [2].

Types of MPS III

MPS III is divided into four different types depending on the defective enzyme. Types A and B are the most common, and type A is the most severe and researched. In comparison, types C and D are rarer and show little deviation in clinical presentation from each other [5]. The differentiation in types may seem minute, but it is actually a leading breakthrough toward finding an effective treatment through gene therapy [6].

Diagnosis

Many families have to heavily advocate for their child to finally receive a proper Sanfilippo syndrome diagnosis. Early detection is key for certain therapies to be effective, but due to the overlap of Autism Spectrum Disorder (ASD) and Attention Deficit/Hyperactivity Disorder (ADHD) symptoms, patients are often misdiagnosed while the disease progresses [3]. This confusion stems from the complexity of the disorder and that most primary care physicians are unfamiliar with the disease and simply do not know the symptomatology. Differential diagnoses are extremely frustrating, time-consuming, and require multitudes of patience. When a parent or caregiver starts to notice a change in their child’s behavior and brings them to their primary care doctor, the most logical approach is to begin pursuing more common diagnoses. After treatment options have been tried to no avail, then a referral to a specialist, like a child neurologist, would be the next step. Even then, a proper diagnosis requires eliminating rare, but still more common than Sanfilippo, neurodegenerative diseases like multiple sclerosis, cerebral palsy, brain tumors, or even lead poisoning. Only child neurologists have the breadth of knowledge to pursue a Sanfilippo diagnosis, and it is often the last resort due to its rarity. 

Increased sugar levels in a child’s urine are the most efficient indicator for Sanfilippo syndrome. Unfortunately, these results can be misleading since not all patients experience elevated levels of sugar, especially if the disease has not advanced. The only concrete diagnostic method is genetic sequencing of the child and parents’ genome [2]. The misordering or mismatching of genetic structures causes gene mutations and defective enzymes [7]. The exact order of genetic structures reveals whether the child has the specific gene mutation and determines their defective enzyme and type of MPS III [2]. Unfortunately, this lengthy and expensive process is not a viable option for every family. Researchers have recently identified a more accessible test for Type A MPS III. The test was effective in its preliminary use and compares the enzymatic activity of sulfamidase, the enzyme that breaks down heparan sulfate, of healthy newborn babies to known Type A patients. The study tested dried blood spots for their enzyme activity and found that healthy newborn babies had significantly higher sulfamidase activity than known Type A patients. This test has yet to enter the clinical trial phase, but it will hopefully be of use in the future to streamline the diagnosis process [8].

Prognosis

The Three Phases of Sanfilippo Syndrome

Sanfilippo syndrome is a progressive disease characterized by three distinct phases. The first consists of developmental delays, usually from one to four years old. These delays can include speech; gross, fine, and oral motor; or cognitive impairment. The second phase is characterized by behavioral difficulties and begins when a patient is three to five years old. This phase can last up to ten years, though may be as short as four years for type A patients because of the disease’s more rapid progression. The final stage results in severe loss of intellectual and motor functions. Children eventually lose their ability to walk and speak, experience seizures, and spend the rest of their lives in a vegetative state. During the final phase, many other medical complications arise since the CNS has eroded beyond functional capacity. Pneumonia is responsible for more than 50% of Sanfilippo syndrome deaths, while cardiorespiratory failure makes up 11% of deaths [9].

Life Expectancy

The average life expectancy of a child with Type A Sanfilippo syndrome is 15.22 years; however, a recent study found that the longevity of Type A patients has improved significantly with no current interventions targeting the underlying structural changes. Patients with Types B and C live an average of 18.91 and 23.43 years, respectively. At the time of publication, no data were available regarding the life expectancy of Type D patients, likely because it is the rarest type [9]. More research and interventions are needed to improve the quality of life for patients suffering from late-stage complications. Families deserve to have their loved one alive and comfortable for as long as possible.

In Comparison to Alzheimer’s Disease (AD)

Sanfilippo and AD have similar pathophysiologies where in both instances the brain has a surplus of proteins or sugars. AD is characterized by the accumulation of the tau protein as opposed to a deficient enzyme. The tau accumulation leads to plaque buildup that inhibits neurons to send and receive signals [10]. Families of AD and Sanfilippo patients both understand the frustration due to the lack of understanding of how these diseases progress so quickly and their intricate mechanisms. In contrast, AD is much more prolific being the sixth leading cause of death, and over 30 million people have been diagnosed. These patients typically range from 65 to 85 years of age [11].

Treatments

While there is currently no cure for Sanfilippo syndrome, research has improved methods to alleviate hyperactivity and behavioral symptoms. A current remedy under development is enzyme replacement therapy (ERT), which directly addresses the dysfunction of sulfamidase, the enzyme affected by Sanfilippo syndrome. One study found that injecting modified sulfamidase directly into the brain or cerebrospinal fluid, the fluid surrounding the brain and spinal cord, helped to alleviate symptoms and emphasize the importance of early detection. The only issue with the therapy is the invasiveness of the procedure. The blood-brain barrier (BBB) serves as the brain’s protector by filtering out potentially harmful substances. This comes as a disadvantage in that sulfamidase is unable to cross the BBB and reduce brain damage when injected into a vein or orally administered. Thus, modified sulfamidase must be directly injected into the brain in order to bypass the BBB [6].

Gene therapy is another promising scientific development that uses elements of enzyme replacement therapy. This medium injects sulfamidase via a virus to force cells to regain the missing enzymatic activity needed to break down heparan sulfate. The manipulated cells are secreted into the bloodstream to recruit and “teach” the defective cells how to regain their enzymatic activity. This treatment showed positive results in mouse models by improving cognitive and motor functions and is now in the human clinical trial phase [6].

Looking To The Future

 Rare disease research as a whole is grossly underfunded by the United States Government, and Sanfilippo syndrome only receives a minuscule amount of that money. Even so, since 2011, the federal funding for rare disease research has almost doubled to $6.2 billion in 2019 in comparison to Alzheimer’s Disease which received $2.2 billion in 2019 alone [12]. Parents and caregivers are so desperate for any resources they can get. A cure is obviously the end goal but even more, research to reduce symptoms and increase life expectancy is urgent. Resources for parents and caregivers are crucial to ensure that their child is able to live out their last days peacefully surrounded by family and friends. Robust funding and research are absolutely necessary to destroy the silent monster that is Sanfilippo syndrome. No parent should have to worry about how their genetic makeup could potentially wreak havoc on their family. No sibling should have to watch their brother or sister whither away before their eyes. No doctor should have to say, “There are no more options left.” A step toward a cure for Sanfilippo syndrome is a step forward for all suffering from a rare disease to recieve the care and life they deserve.

References:

1. National Institute of Health. (n.d.). Mucopolysaccharidosis type III - about the disease. Genetic and Rare Diseases Information Center. Retrieved November 28, 2022, from https://rarediseases.info.nih.gov/diseases/3807/mucopolysaccharidosis-type-iii 

2. Valstar, M. J., Ruijter, G. J. G., van Diggelen, O. P., Poorthuis, B. J., & Wijburg, F. A. (2008). Sanfilippo syndrome: A mini-review. Journal of Inherited Metabolic Disease, 31(2), 240–252. https://doi.org/10.1007/s10545-008-0838-5

3. Research Help Explain Autism-Like Symptoms in Sanfilippo. Sanfilippo Children's Foundation. (2021, July 21). Retrieved November 5, 2022, from https://www.sanfilippo.org.au/blog/research-helps-explain-autism-like-symptoms- in-sanfilippo#:%7E:text=In%20the%20earlier%20stages%20of,their%20exact%2 0cause%20is%20unknown. 

4. Platt, F. M., Boland, B., & van der Spoel, A. C. (2012). Lysosomal storage disorders: The cellular impact of lysosomal dysfunction. Journal of Cell Biology, 199(5), 723–734. https://doi.org/10.1083/jcb.201208152

5. Carroll, R. S. (Ed.). (2019, September). Sanfilippo syndrome (for parents) - nemours kidshealth. Retrieved November 5, 2022, from https://kidshealth.org/en/parents/sanfilippo-syndrome.html#:%7E:text=What%20I s%20Sanfilippo%20Syndrome%3F,cure%20yet%20for%20Sanfilippo%20syndro me. 

6. Fedele, A. (2015). Sanfilippo syndrome: causes, consequences, and treatments. The Application of Clinical Genetics, 8, 269-281. https://doi.org/10.2147/tacg.s57672

7. Human genome project fact sheet. Genome.gov. (n.d.). Retrieved September 27, 2022, from https://www.genome.gov/about-genomics/educational-resources/fact-sheets/human-genome-project 

8. Yi, F., Hong, X., Kumar, A. B., Zong, C., Boons, G.-J., Scott, C. R., Turecek, F., Robinson, B. H., & Gelb, M. H. (2018). Detection of mucopolysaccharidosis III-A (sanfilippo syndrome-A) in dried blood spots (DBS) by Tandem Mass Spectrometry. Molecular Genetics and Metabolism, 125(1-2), 59–63. https://doi.org/10.1016/j.ymgme.2018.05.005 

9. Lavery, C., Hendriksz, C. J., & Jones, S. A. (2017). Mortality in patients with Sanfilippo syndrome. Orphanet Journal of Rare Diseases, 12(1). https://doi.org/10.1186/s13023-017-0717-y 

10. Kumar, A., Singh, A., & Ekavali. (2015). A review on alzheimer's disease pathophysiology and its management: An update. Pharmacological Reports, 67(2), 195–203. https://doi.org/10.1016/j.pharep.2014.09.004 

11. Haque, R. U., & Levey, A. I. (2019). Alzheimer’s disease: A clinical perspective and future nonhuman Primate Research Opportunities. Proceedings of the National Academy of Sciences, 116(52), 26224–26229. https://doi.org/10.1073/pnas.1912954116

12. National Institutes of Health. (2022, May 26). Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC). National Institutes of Health. Retrieved November 28, 2022, from https://report.nih.gov/funding/categorical-spending#/