This study characterises morbidity and mortality in patients with ASMD type B or type A/B in a German cohort. While a previous study by McGovern et al. reported a detailed description of the major morbidities and causes of death in patients with chronic ASMD in the United States [19], the current study adds data from a German cohort, highlighting substantial morbidity and mortality associated with ASMD. Most importantly, this study reports the survival analysis of patients stratified by the type of ASMD.

In this study population, the proportion of female patients (54.5%) and the mean age at the first symptom onset and diagnosis (7.0 and 11.5 years, respectively) were slightly higher than findings from previous prospective, cross-sectional survey studies on patients with chronic ASMD [21]. McGovern et al. reported a population of 47.5% female patients with chronic ASMD, and the mean age at the first symptom onset and diagnosis was 5.0 and 9.8 years, respectively [21].

High mortality was observed in this German population, with a mortality rate of 27.3%. Overall, 66.7% of the deceased patients were aged less than 18 years at death; this included four patients with ASMD type A/B and two with ASMD type B. The mean age at death for overall nine deceased patients was 21.2 years. A previous report [19] has reported a mean age at death of 25.0 years for patients with chronic ASMD. The mean age at death for patients with ASMD type A/B (11.7 years) was lower than that for patients with ASMD type B (33.1 years). Similar observation was reported earlier by Cassiman et al. [8].

The results are also consistent with reported causes of death in patients with ASMD type B or type A/B [8, 22]. Cassiman et al. reported the leading causes of death as respiratory and liver failure, irrespective of age among patients with ASMD type B or type A/B [8]. Other reported causes of death were bleeding complications (which might be related in some cases to liver failure) and complications from bone marrow transplants, multi-organ failure, heart failure, and liver cancer [9]. Pneumonia was reported as the most common cause of death in patients with chronic ASMD by McGovern et al., 2021 [22]. Similar causes of death were noted in the overall ASMD population in the current study, primarily liver disease (22.2%), respiratory disease (22.2%, including respiratory failure, insufficiency, pneumonia, pulmonary embolism, and others), severe progressive neurodegeneration (22.2%), bleeding (11.1%), multi-organ failure (11.1%), and others (11.1%). Severe progressive neurodegeneration (40.0%), liver disease (20.0%), respiratory failure (20.0%), and other causes (20.0%), were reported as the causes of death in patients with ASMD type A/B (n = 5). These results are consistent with those presented by Cassiman et al., suggesting neurodegenerative disease (23.1%) along with liver disease (19.2%) and respiratory failure (23.1%) are the primary causes of death in patients with ASMD type A/B [8].

The current study further highlights the high incidence of morbidity associated with the splenic, hepatic, and respiratory findings in patients with ASMD, similar to previous reports [5, 8, 22]. All patients had at least one reported clinical finding/complication during the observation period, and 57.6% had an ASMD-related hospitalisation indicating high disease severity. These findings underline the need for regular clinical assessment in patients with ASMD. Common disease-related morbidities included splenomegaly (96.9%), hepatomegaly (96.8%), and interstitial lung disease (75.0%). A previous report involving patients with ASMD type B and A/B reported similar disease-related morbidities, including splenomegaly (96.6%), hepatomegaly (91.4%), liver dysfunction (82.6%), and pulmonary disease (75.0%) [8]. Another study involving chronic ASMD has reported splenomegaly (78.0%) and hepatomegaly (73.0%) as the most common clinical findings at the initial visit [10, 21]. A study involving the Dutch and Belgian patient populations with ASMD reported interstitial abnormalities in the lungs in 81.3% of patients with ASMD [23]. In the current study, liver and respiratory manifestations were mostly reported in ASMD type B. McGovern et al. [19] also reported liver disease and pulmonary disease as major morbidities in ASMD type B. Thus, patients with chronic ASMD display wide phenotypic heterogeneity, including a broad spectrum of disease manifestations and severity levels [1].

For life-threatening conditions present since birth, the KM analysis might be prone to left truncation as only patients alive until diagnosed with ASMD were included in the study. Therefore, the KM curve with adjusted analysis was performed to estimate the survival probability to avoid an overestimated survival. By conditioning the survival estimate on the age at diagnosis, the adjusted analysis was conducted to avoid the bias and hence, to present a more accurate estimate of survival. Given the rarity of ASMD, alternative methods of survival analysis may be helpful to address the limitations associated with small sample size and heavy censoring [22]. The overall SMR (95% CI) in patients with ASMD type B and type A/B indicated that the German ASMD population had 21.6 times more deaths than the age-specific mortality rates in the general population. Despite the steady increase in German life expectancy [24], our results indicate a large unmet need for better treatment options for patients with ASMD.

It is imperative for healthcare providers, policymakers, and the ASMD community to recognise the substantial impact of ASMD. Efforts aimed at improving diagnosis and expanding access are essential to ensure timely intervention to improve quality and extend life expectancy of patients living with ASMD.

The following limitations should be considered while interpreting the findings from this study. The study relied on retrospective data collected from available medical records. The findings are based on secondary data not collected for the purposes of this study. The study had a relatively small sample size. Only seven patients were above 6 years of age at the first evidence of the disease, and nine patients with ASMD type A/B were included, thereby impacting the generalisability of the findings. Further, the available data on clinical parameters were sparse because of missing information in the medical records; this was attributed to a lack of unified medical record systems and patients seeking care at multiple facilities. Liver function tests were analysed only at the first date of evidence (follow-up data were not retrieved); they were not standardised, nor were they performed by a central laboratory, thereby introducing variability. Absence of clinical guidelines for monitoring or managing patients with ASMD type B and A/B during the study duration may have contributed to infrequent examinations and assessments; hence, some examinations and assessments might not have been regularly performed and reported, as currently recommended in recent guidelines [7, 25]. Additionally, hospitalisation records in local hospitals might not be well documented, leading to underreporting hospitalizations. The OS for patients with ASMD type B was based on a limited number of events (n = 4) during the observation time. Heavy censoring was noted in these patients by the age of 35 years, leaving only a few patients at risk. This study used SMR analysis as an alternative approach to estimate OS. However, its calculation also relies on the available information from the patient charts and assumes a constant increase in mortality risk across ages and might not accurately represent the shape of the survival function for patients with ASMD type B or type A/B.