Sanfilippo syndrome – the childhood dementia

What is Sanfilippo syndrome?

Sanfilippo syndrome, or mucopolysaccharidosis Type III (MPS III), is a rare form of childhood dementia with an estimated prevalence of 1:250,000.(1) There are 4 subtypes of Sanfilippo syndrome, known as Type A, B, C, and D.(2) The lysosome is a sac in the body containing enzymes that break down the naturally produced sugar, heparan sulphate.(3,4) Each subtype has a defective gene and subsequently insufficient enzyme levels to break down heparan sulphate, leading to its the accumulation in the cell and?impairing its function.(2–5) The life expectancy in patients with Sanfilippo syndrome is very poor with most passing away in their early teens.(1)

Each subtype has its own clinical progression.(2) Subtype A is the most common and severe form, whilst subtype C is milder with a slower disease progression.(2) The clinical features of Sanfilippo syndrome become more prominent as the disease progresses and include:(1,5)

· Increased coarseness of facial features (absence of fine and sharp facial features)

·???????Decline in intellectual ability

·???????Brain atrophy (shrinking of the brain)

·???????Loss of ability to eat

·???????Impaired mobility

·???????Sleep disturbance

·???????Aggressive, hyperactive, and impulsive behaviour

·???????Seizures

·???????Hearing loss

·???????Enlargement of the liver and spleen

Getting the correct diagnosis

Delayed diagnosis often occurs as the result of an initial misdiagnosis (e.g., autism), as Sanfilippo syndrome is not routinely screened for at birth.(1) In 2020, a consensus of the early signs of Sanfilippo syndrome was agreed to help reduce delays in diagnosis.(4) These include:(4)

1.??????Coarse facial features

2.??????Persistent hirsutism (dark coarse hair) or thick distinctive eyebrows

3.??????Breathing problems in the first week of life

4.??????Frontal bossing with macrocephaly (prominent forehead and larger than normal head size)

5.??????Gastrointestinal discomfort and colic

6.??????Umbilical or inguinal hernia (swelling in the groin)

7.??????Frequent upper respiratory congestion (blocked nose)

8.??????Increased food intake or nursing

Once the early signs of Sanfilippo syndrome are identified, patients should be referred to a specialist for heparan sulphate, lysosomal enzymes, and genetic testing.(1) A diagnosis is made if genetic testing and one of the other tests turns out positive.(1)

Unfortunately, most patients with Sanfilippo syndrome receive a diagnosis after 2 years of age.(1) A delayed diagnosis is detrimental to patients as support interventions are most effective when started prior to cognitive decline.(1) As Sanfilippo syndrome is inherited, early diagnosis allows families to receive genetic counselling about how this diagnosis may influence family plans.(1) Greater awareness of this disease is needed to aid early diagnosis.(1,4)

Clinical management of Sanfilippo syndrome

Currently, there is no cure or treatment to slow the progression of this disease.(2) Prior to 2022, no consensus guidelines on the clinical management of patients with Sanfilippo syndrome existed.(1) Such guidelines are imperative for a prompt diagnosis and to ensure the best standard of care for patients.(1) Patients with Sanfilippo syndrome have a wide range of complex medical needs that require a team of healthcare professionals, including:(1)

·???????Physicians

·???????Nurses

·???????Physical, occupational, and speech therapists

·???????Psychologists

·???????Social workers

·???????Special educators

·???????Dieticians

Supportive interventions include speech and physical therapies which aim to maintain existing skills rather than gain new skills.(1) It is important that caregivers receive support, such as counselling, to allow them to best support their child.(1,6,7) The development of new treatments and updated best practice guidelines is important as 22% of caregivers of children with Sanfilippo syndrome were diagnosed with post?traumatic stress disorder as a result of traumatic medical events happening to their child.(6)

Clinical trials for new treatments

Clinical trials can offer hope to caregivers as they offer the only hope of slowing down the progression of the disease.(7) There are 3 main types of treatment in clinical trials:(5,8)

1.??????Enzyme replacement therapy (ERT) – which works by regularly injecting the missing enzyme either into the bloodstream or into the brain. However, new delivery methods are needed to ensure enough enzyme enters the brain

2.??????Substrate reduction therapy (SRT) – aims to use daily injections to silence the gene producing heparan sulphate and preventing its accumulation in cells

3. Gene therapy –a harmless virus known as adeno-associated virus (AAV) could be used to deliver the gene encoding the missing enzyme into the body. This treatment would require one injection into the brain, cerebrospinal fluid, or bloodstream

Barriers to a cure for Sanfilippo syndrome

The biggest barrier to the successful treatment of Sanfilippo syndrome is the small number of clinical trials.(5) In the past 20 years, there have been just 26 clinical trials outperformed worldwide, with only 9 being carried out until completion.(5) Clinical trials for Sanfilippo syndrome are very small, often with as little as 5 patients.(2) Their small sample size and the variable clinical presentation of patients hinders the interpretation of the results.(2) Parents are aware of the high risks of clinical trials, but advocated for less stringent inclusion criteria.(7) This variability could be reduced by having subtype-specific clinical trials, but this requires a better understanding of disease presentation and progression in different subtypes.(2)

Currently, there is no consensus on what criteria would need to be assessed and achieved to make a therapy ‘effective’ according to regulatory authorities.(2) The ideal therapy would be able to reverse the decline in cognition.(2) A survey of 25 parents of children with Sanfilippo syndrome highlighted that even modest improvements in symptoms and quality of life are extremely valuable.(7) Therefore, parents felt clinical trials should focus on quality of life rather than cognitive outcomes as they would highly value a treatment that would slow or stop cognitive decline.(2,7)

A further barrier to the development of an effective treatment is that clinical trials are often designed to be short-term but Sanfilippo syndrome, by its very nature, progresses slowly.(2) Long-term clinical studies are needed but there is a requirement for biomarkers that predict long-term clinical outcomes early in the course of treatment, especially since most treatments are not effective.(2)

Summary

Sanfilippo syndrome is a rare genetic disease that causes childhood dementia and has a poor life expectancy.(5) The road to a diagnosis can be long and difficult due to a lack of awareness about the disease.(1) Only recently guidelines were developed for the clinical management of Sanfilippo syndrome and these need to be updated regularly to ensure the best quality of care for these patients.(1) As there is no cure, there is an urgent need for new treatments that can help improve the quality of life of patients with Sanfilippo syndrome.(5)

References

1.???????????Muschol N, Giugliani R, Jones SA, Muenzer J, Smith NJC, Whitley CB, et al. Sanfilippo syndrome: consensus guidelines for clinical care. Orphanet J Rare Dis. 2022;17:391.

2.???????????Ghosh A, Shapiro E, Rust S, Delaney K, Parker S, Shaywitz AJ, et al. Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III. Orphanet Journal of Rare Diseases. 2017;12(117).

3.???????????Selemin J. What Is Sanfilippo Syndrome? [Internet]. WebMD. [cited 2023 Jan 24]. Available from: https://www.webmd.com/children/what-is-sanfilippo-syndrome

4.???????????Escolar M, Bradshaw J, Byers VT, Giugliani R, Golightly L, Louren?o CM, et al. Development of a Clinical Algorithm for the Early Diagnosis of Mucopolysaccharidosis III. J inborn errors metab screen. 2020;8.

5.???????????Pearse Y, Iacovino M. A Cure for Sanfilippo Syndrome? A Summary of Current Therapeutic Approaches and their Promise. Med Res Arch. 2020;8(2).

6.???????????Conijn T, Nijmeijer SCM, van Oers HA, Wijburg FA, Haverman L. Psychosocial Functioning in Parents of MPS III Patients. Morava E, Baumgartner M, Patterson M, Rahman S, Zschocke J, Peters V, editors. JIMD Reports. 2019;44:33–41.

7.???????????Porter KA, O’Neill C, Drake E, Parker S, Escolar ML, Montgomery S, et al. Parent Experiences of Sanfilippo Syndrome Impact and Unmet Treatment Needs: A Qualitative Assessment. Neurol Ther. 2021;10(1):197–212.

8.???????????Sanfilippo Children’s Foundation [Internet]. Sanfilippo. [cited 2023 Jan 24]. Available from: https://www.sanfilippo.org.au/research/therapy-avenues.

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