Diagnostic Delays in Sanfilippo Syndrome Haven’t Improved in Nearly 3 Decades in Netherlands, Study Reports

The time it takes to diagnose mucopolysaccharidosis (MPS) type III, or Sanfilippo syndrome, haven’t improved in nearly three decades in the Netherlands and persists as a problem that must be resolved, researchers reported.

Campaigns to raise awareness and reduce diagnostic delays have failed in the Netherlands and implementing screening programs for the disorder may be the only effective approach to shorten the time to diagnosis and initiate timely treatment.

The study, “Failure to shorten the diagnostic delay in two ultra-orphan diseases (mucopolysaccharidosis types I and III): potential causes and implications,” was published in the Orphanet Journal of Rare Diseases.

Correct diagnoses are often too long in coming in rare diseases like Sanfilippo syndrome. Due to their rarity and often nonspecific symptoms, a diagnosis is not achieved or is given incorrectly for extended periods of time.

These diagnostic delays may significantly add to the disease burden of patients and caregivers. An early diagnosis is particularly essential if a disease-modifying treatment is available.

In the case of Sanfilippo syndrome, no disease-specific therapies are available yet, but several promising treatments are being explored, including gene therapy and enzyme replacement therapy (ERT).

A number of campaigns such as Rare Disease Day have been launched worldwide to raise rare disease awareness in the general population and among healthcare professionals. But no studies have specifically investigated whether these campaigns have been able to reduce the time to diagnosis.

To assess diagnostic delays for MPS I (Hurler syndrome) and MPS III in the Netherlands from 1988 to 2017 — the time between the first visit to a medical specialist for disease-related symptoms and the final diagnosis — researchers conducted telephone interviews with patients or their legal guardians. Medical records of these patients were also reviewed.

The study was conducted at the Academic Medical Center (AMC) in Amsterdam, a center of expertise for MPS I and MPS III in the Netherlands.

A total of 29 patients with MPS I and 46 patients with MPS III were included, both groups containing patients with different levels of disease severity.

The Sanfilippo group included individuals with MPS IIIA,  MPS IIIB, and MPS IIIC, and patients with severe rapidly progressing and more attenuated, slowly progressing disease.

For MPS III, time to diagnosis was typically longer than for MPS I, with a median diagnostic delay of 33 months. Overall, it took between one to 365 months for Sanfilippo patients to get a correct diagnosis.

Almost all MPS III patients (45 of the 46 analyzed) were first brought to a general practitioner at a median age of 22 months. The most common symptoms that led parents to take their children to the doctor were upper airway infections and middle ear problems.

Later, at a median age of 28 months, the ailing children were seen by a medical specialist, most often by an ear, nose, and throat specialist. Yet in most children, several MPS III symptoms were already present.

A final diagnosis was only achieved at a median age of 62 months (roughly five years). Rapidly progressing patients were significantly younger at the time of diagnosis compared to slower progressing children — 54 months vs. 71 months, respectively. 

However, disease severity did not change the delay in diagnosis (a median of 33 months).

Importantly, when researchers compared the diagnostic delays over time using five-year time intervals, there was no reduction in the time to diagnosis from 1988 to 2017.

Researchers note that awareness campaigns dedicated to rare diseases in general, and to MPS disorders in particular, have failed to reduce the long delays in diagnosis, a problem that still persists.

“Because most medical doctors will probably visit with patients with these disorders never, or only once during their entire career, it is questionable whether education of combinations of symptoms of specific (ultra) rare diseases will ever be effective,” researchers wrote.

“Robust selected screening protocols embedded in national guidelines may be the best alternative,” they added.

These guidelines may include urinary screening for glycosaminoglycans — the sugar molecules that accumulate in the cells of patients with mucopolysaccharidosis — and extensive screening for inborn errors of metabolism in children with MPS-related symptoms.

“Finally, [newborn screening] should be considered for those disorders that meet the criteria for population screening because this may be the only approach to guarantee a timely initiation of therapy in all patients with specific rare diseases,” researchers wrote.