In this study, we described mortality figures and survival referring to a substantial number of patients diagnosed with a rare disease, and who were enrolled in a population-based registry. Mortality data and observed trends over time are particularly informative as they can document outcomes over the patients’ lifetime and/or areas of unmet needs requiring investments in research and care. Our study showed that RD patients experience higher crude mortality rates than the general population, especially in the older age groups. This finding is in line with previous figures provided by our registry referring to a 10-year observation period [26] and with results from a study carried out in another Italian region, where a similar RD registry has been established [31]. Mortality rates progressively increasing with age can be explained by the accumulation of damage involving many vital systems and organs and by the occurrence of elderly-onset comorbidities, both in the RD and general population. Unfortunately, no information was available in our study on the presence or absence of comorbidities, potentially affecting the observed trends. The observed pediatric mortality peak in the age group of 1–4 years old (4.56 per 100,000) is in relative agreement with evidence from an Irish hospital-based study reporting a significant contribution of RD to pediatric mortality [18]. Interestingly, when standardizing for age, female patients were found to have an increased risk of death than their male counterparts, compared to the general population, 2.01 versus 1.86. This gender difference certainly deserves further study to better understand the intertwining of purely biological factors and factors related to delayed diagnosis and access to treatment and care, as reported in women affected by other conditions.

Our study showed a diverse contribution of different rare disease groups to mortality figures in the monitored population. Patients with diseases belonging to the following Orphanet classifications emerged as the ones affected by higher mortality rates: rare neurologic diseases, systemic or rheumatologic diseases and rare skin diseases.

These findings are not directly comparable with the ones based on data derived from our Registry from 2002 to 2012 for three main reasons. First, the list of RD that undergo mandatory monitoring in Italy was updated in 2017, introducing new RD entities, such as respiratory diseases (i.e. sarcoidosis, idiopathic pulmonary fibrosis, idiopathic pulmonary hypertension) and rheumatologic diseases such as systemic sclerosis, impacting overall and group-related mortality figures. Second, since 2012 we have witnessed impressive changes in the preventive, diagnostic and care field, such as the use of innovative genetic tests, the implementation of neonatal screening policies, and the availability of innovative treatments, although this is still only for a limited proportion of RD. The effects of all these changes may have impacted the survival of the monitored population, especially in selected disease groups. Third, in our previous study and the study exploring RD patient survival in the Tuscany region, disease categorization was based on ICD groups.

As RD are under-represented in ICD, they are usually under-reported in mortality studies. In the forthcoming ICD-11 this problem will be mitigated, allowing in the future to properly estimate RD contribution to mortality in the general population. In the meantime, the use of ORPHAcodes, a specific RD coding resource, helps provide a snapshot of the contribution of diverse disease groups to RD epidemiologic figures.

Thanks to the use of ORPHAcodes, we were able to highlight the impact on patient survival of specific subgroups of diseases within broader categories, as is the case of lysosomal storage diseases. Although in some cases neonatal screening policies include these diseases, and despite the availability of innovative treatments, it is important to report that affected patients still experience reduced survival.

Another group of patients presenting highly reduced survival rates are those diagnosed with rare neurologic diseases. This is mainly attributable to adult and elderly patients with ALS and to pediatric patients diagnosed with SMA. Several studies have investigated ALS survival in selected populations, using data either from disease registries or from population-based registries [32].

Our study findings are in accordance with previous studies; however, we also identify ALS contribution to overall mortality figures referring to a wider RD population.

Along with ALS patients, SMA patients experience a severe disease course, especially SMA type I patients, for whom a median life expectancy of less than 2 years without respiratory support has been reported [33]. This disease trajectory is confirmed by our study.

According to our study findings, overall, only 18% of patients diagnosed with motor neuron diseases were alive after a 15-years observation period.

Recently, SMA patients have benefitted from the availability of new disease-modifying treatments, in particular SMA type I children. Along with these new therapies, neonatal screening for this condition is already performed in some countries/regions, and is under discussion in others [34]. Some evidence of survival benefit following the introduction of these therapies, besides clinical trial data, is available [35]. Nevertheless, more data are needed from real-world population-based studies with long-time observation periods so that a comparison can be made between cases before and after (1) the introduction of neonatal screening and (2) access to these therapeutic options.

The same applies to rare respiratory diseases, a group of diseases which generally affects adult and elderly patients and is among the diseases presenting reduced patient survival in the present study. To what extent new available therapies and improved access to lung transplantation has an impact on patients’ long-term survival is an important research question requiring further study.

Although rare skin diseases were diagnosed in a minority (5.2%) of all the patients enrolled in the Registry during the study period, very poor survival rates can be observed in this subset of patients. This is in line with previous studies investigating survival, although in distinct rare skin diseases [36, 37]. What this study adds is their overall contribution to mortality figures in the population under study.