Rare diseases are often un- or misdiagnosed for extended periods, resulting in a long diagnostic delay that may significantly add to the burden of the disease. An early diagnosis is particularly essential if a disease-modifying treatment is available. The purpose of this study was to assess the extent of the diagnostic delay in the two ultra-rare diseases, i.e., mucopolysaccharidosis I (MPS I) and III (MPS III), both of which are lysosomal storage disorders with different phenotypic severities (MPS 1 is characterized by the severe Hurler and the more attenuated non-Hurler phenotypes, MPS III is characterized by the severe rapidly progressing (RP) phenotype and more attenuated slowly progressing (SP) phenotype). We investigated whether the diagnostic delay changed over the previous decades. The diagnostic delay, which is defined as the time between the first visit to a medical doctor for disease-related symptoms and the final diagnosis, was assessed using telephone interviews with patients diagnosed between 1988 and 2017 and/or their parents or legal guardian(s). In addition, the medical charts were reviewed. For MPS I (n = 29), the median diagnostic delay was 8 months (range 1-24 months) for Hurler patients and 28 months (range 2-147 months) for non-Hurler patients. For MPS III (n = 46), the median diagnostic delay was 33 months (range 1-365 months). No difference was observed between the RP and SP phenotypic groups. Comparing the diagnostic delay over time using 5-year time intervals, no reduction in the diagnostic delay was observed for MPS I or MPS III. In the Netherlands, the time to diagnosis for patients with MPS I and MPS III has not changed between 1988 and 2017, and an extensive delay still exists between the first visit to a medical doctor for disease-related symptoms and the final diagnosis. The numerous campaigns launched to increase awareness, leading to earlier diagnosis of these rare disorders, particularly of MPS I, have failed to achieve their goal. Robust selected screening protocols embedded in national guidelines and newborn screening for disorders that meet the criteria for population screening may be the only effective approaches for reducing the diagnostic delay.

Background: Mucopolysaccharidosis type IIIB (MPS IIIB) is a rare genetic disorder in which the deficiency of the lysosomal enzyme N‐acetyl‐α‐glucosaminidase (NAGLU) results in the accumulation of heparan sulfate (HS), leading to progressive neurocognitive deterioration. In MPS IIIB a wide spectrum of disease severity is seen. Due to a large allelic heterogeneity, establishing genotype‐phenotype correlations is difficult. However, reliable prediction of the natural course of the disease is needed, in particular for the assessment of the efficacy of potential therapies.Methods: To identify markers that correlate with disease severity, all Dutch patients diagnosed with MPS IIIB were characterised as either rapid (RP; classical, severe phenotype) or slow progressors (SP; non‐classical, less severe phenotype), based on clinical data. NAGLU activity and HS levels were measured in patients’ fibroblasts after culturing at different temperatures.Results: A small, though significant difference in NAGLU activity was measured between RP and SP patients after culturing at 37 °C (p < 0.01). Culturing at 30 °C resulted in more pronounced and significantly higher NAGLU activity levels in SP patients (p < 0.001) with a NAGLU activity of 0.58 nmol.mg‐1.hr‐1 calculated to be the optimal cut‐off value to distinguish between the groups (sensitivity and specificity 100 %). A lower capacity of patients’ fibroblasts to increase NAGLU activity at 30 °C could significantly predict for the loss of several disease specific functions.Conclusion: NAGLU activity in fibroblasts cultured at 30 °C can be used to discriminate between RP and SP MPS IIIB patients and the capacity of cells to increase NAGLU activity at lower temperatures correlates with disease symptoms.