To the best of our knowledge, this is the first multicenter study to analyze the survival and diagnostic age of patients with various types of MPS in a countrywide population across a 35 year period. We found that the life expectancy and diagnostic age of patients with MPS had improved in recent decades. In Taiwan, the National Health Insurance program was implemented in 1995, the Rare Diseases and Orphan Drugs Act was passed in 2000, and countrywide MPS newborn screening programs were started in 2016 with a median diagnostic age of 0.2 years. Thus, it is possible that the observed improvement in life expectancy may be due to the timely referral of MPS patients to specialists and the early administration of multidisciplinary care, as well as medical advancements in ERT and HSCT.
For Taiwanese patients with MPS in the current cohort, MPS II was the most prevalent subgroup (45%), followed by MPS III (19%), MPS IV (18%), MPS I (12%), and MPS VI (6%). To date, there has been no confirmed patient with MPS VII in Taiwan. The predominance of MPS II in Taiwan (45%) is consistent with other Asian countries, including China (47.4%), Japan (55%), and South Korea (54.6%). However, in most Caucasian populations, MPS III or MPS I is the most prevalent MPS type . The founder effect may explain the differences in MPS type prevalence across various ethnic populations.
The median diagnostic age for patients with all types of MPS was 3.9 years. In the current study, children under five years of age, especially those who were diagnosed through the newborn screening programs and did not have significant clinical manifestations, were not categorized into MPS I and II subgroups (severe vs. mild), due to the difficulty in determining mental development status. For MPS I, the data from the MPS I Registry (n = 891) reported by D'Aco et al.  indicated that the median diagnostic age was 0.8 years for Hurler syndrome, 3.8 years for Hurler-Scheie syndrome, and 9.4 years for Scheie syndrome. In the present study, the median diagnostic age was 1.5 years for all MPS I patients (n = 21). Parini et al.  reported that the median diagnostic age for MPS II was 3.0 years (n = 316) for those with the severe form, and 3.8 years for those with the attenuated form (n = 320). Similarly, the median diagnostic age for all MPS II patients (n = 78) was 3.8 years in the current study. Truxal et al.  reported that the mean diagnostic age for MPS III was 3.4 years (n = 25). In the current study the mean diagnostic age for MPS III was 4.9 years (n = 33). Data from the International Morquio A Registry (n = 311) reported by Montaño et al.  revealed a mean diagnostic age of 4.7 years for MPS IV, which was supported by our results (5.8 years; n = 32). Information on the median diagnostic age for MPS VI patients was lacking in the literature. In the current cohort, the median diagnostic age was 3.7 years (n = 11).
Since MPS is a rare, progressive, multisystemic disease with insidious initial signs and symptoms, making an early diagnosis can be challenging for first-line general practitioners . Newborn screening programs could help provide an early diagnosis for MPS at an asymptomatic age, thus allowing for more timely and appropriate treatment for these patients. Since the pilot newborn screening programs for MPS I, II, VI, IVA, and IIIB were progressively implemented in Taiwan from 2016, up to 94% (16/17) of MPS patients born between 2016 and 2019 have been diagnosed via the programs, with a median diagnostic age of 0.2 years. This is notably lower than the median age at diagnosis of 4.3 years for the other 159 patients diagnosed via clinical indications during the same time period. In the present study, 9 of the 16 patients diagnosed via the newborn screen programs received ERT following their diagnosis; payments for this were reimbursed by the Taiwanese National Health Insurance program according to international standards. In addition, 3 MPS II patients also received HSCT. Following a comprehensive explanation of the progressive nature of MPS and the importance of the early initiation of ERT or HSCT before the occurrence of irreversible organ damage, the parents of the other seven patients elected for their children to receive regular follow-ups every 6 months at the clinic to check for any emerging symptoms of MPS. Although ERT and HSCT cannot cure the disease, they can improve or alleviate its natural progression, and better outcomes may be associated with the early administration of these treatments [20–22]. Since survival time and the natural disease course may be significantly altered in patients who receive early ERT and HSCT, longer follow-up periods are warranted to observe the efficacy of these treatments in children with MPS who are diagnosed early via the newborn screen programs.
The natural disease course and overall prognosis vary among different MPS types and there is a wide spectrum of clinical severity [2, 31, 35–43]. Data from the MPS I Registry (n = 180) reported by D'Aco et al.  revealed that the median age at death for all MPS I patients was 5.1 years (range, 0.4–46.6). In the present study, the median age at death was 15.0 years (n = 6). For MPS II, the most severely affected patients with MPS II usually only survive until their second decade of life, however, less severely affected patients may survive until their fifth or sixth decade of life [35, 36]. The Hunter Outcome Survey (HOS) data (n = 129) reported by Jones et al.  showed that the median age of death was 13.4 years for MPS II. In our study, the median age of death was similar at 14.1 years (n = 46). We also found that the MPS II patients with cognitive impairment had a shorter life span than those without cognitive impairment (13.1 years vs. 18.2 years), which was consistent with previous reports [37, 38]. For MPS III, Lavery et al.  reported that the mean age at death between 1977 and 2007 was 15.2, 18.9 and 23.4 years for patients in the UK with MPS IIIA (n = 84), MPS IIIB (n = 24), and MPS IIIC (n = 5), respectively. Similarly, the present study found that the mean age at death for MPS III (n = 15) was 18.5 years for patients in Taiwan. For MPS IV, Lavery and Hendriksz  reported that the mean age at death was 25.3 years for 27 patients with MPS IVA in the UK between 1975 and 2010. The present study showed that the mean age at death was 17.3 years for patients with MPS IVA (n = 11). For MPS VI, the MPS VI Survey Study reported by Giugliani et al.  showed that the mean age at death for 17 ERT patients and 7 ERT-naive patients was 22.9 and 19.2 years, respectively. The current study showed that the mean age at death for MPS VI (n = 3) was 24.2 years, including two ERT patients who died at 26.6 and 27.6 years, respectively, and one ERT-naive patient who died at 18.3 years. Our results also revealed that ERT may lengthen the life expectancy of patients with MPS VI.
In the current study, the age at diagnosis was positively correlated with life expectancy (p < 0.01). A possible explanation for this might be that MPS has a broad spectrum of disease severity, and that patients with a milder form may manifest more subtle clinical signs and symptoms leading to a delay in their diagnosis or even a misdiagnosis with other disorders, as well as longer survival.
In the current study, the life expectancy for patients significantly increased between 1985 and 2019, however this increase was gradual (p < 0.01). In keeping with this finding, Jones et al.  reported in the HOS that the median age at death was significantly lower in patients who died in or before 1985 compared with those who died after 1985 (11.3 vs. 14.1 years, p < 0.001). Sohn et al.  also reported that patients who died after 2005 lived significantly longer than those who died before 2005 (19.4 vs. 11.4 years, p < 0.05). This may reflect advancements in medical care, early diagnosis, and appropriate treatment for MPS patients over the past few decades.
As a retrospective, multicenter study, some medical records were missing and were not available at the time of this study. The relatively small sample size for each type of MPS in this cohort reflects the rare nature of this genetic disorder, and the degree of disease severity was quite wide. Consequently, studies with a larger study cohort and a longer follow-up period are warranted to validate these findings.